@article {pmid41680609,
year = {2026},
author = {Pourhossein, S and Mianrood, IB and Khatami, SH and Ehtiati, S and Ghasemian, M and Mokhtari, F and Ahmadzade, R and Goudarzi, M and Hamed, N and Namvarjah, F and Karima, S},
title = {Acetyl-11-keto-β-boswellic acid attenuates tau oligomer-induced neurotoxicity in neuroblastoma cell model.},
journal = {BMC neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12868-026-00996-6},
pmid = {41680609},
issn = {1471-2202},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by microtubule destabilization, neuroinflammation, and tau pathology. Among the proposed therapeutic approaches, acetyl-11-keto-β-boswellic acid (AKBA), a bioactive triterpene from Boswellia serrata, has gained attention due to its multiple neuroprotective mechanisms, including microtubule stabilization, anti-inflammatory activity, antioxidant effects, and promotion of neurogenesis. In this study, we aimed to investigate the neuroprotective effect of AKBA against tau oligomer-induced cytotoxicity in SH-SY5Y neuroblastoma cells.

RESULTS: Recombinant human tau protein was expressed, purified, and oligomerized, and the formation of oligomers was confirmed by thioflavin T fluorescence and dynamic light scattering (DLS). SH-SY5Y cells were then treated with AKBA and exposed to tau oligomers. Cell viability was assessed via MTT assay, and apoptosis was evaluated by flow cytometry. The morphology of tau aggregates was visualized using transmission electron microscopy.

CONCLUSIONS: Our findings demonstrated that AKBA significantly reduced tau oligomer-induced cytotoxicity and enhanced cell viability. These results suggest that AKBA, through its multifaceted protective mechanisms, holds promise as a potential therapeutic agent for the treatment of tauopathies such as Alzheimer's disease.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid41680597,
year = {2026},
author = {Roh, HW and Chang, YY and Kim, KY and Jeon, SY and Wang, SM and Kim, E and Bae, JN and Ryu, SH},
title = {Evolving Alzheimer's Disease Clinical Practice: Updated Diagnostic Criteria, Fluid Biomarkers, and Special Considerations for Anti-Amyloid Therapies.},
journal = {Psychiatry investigation},
volume = {23},
number = {2},
pages = {183-200},
doi = {10.30773/pi.2025.0400},
pmid = {41680597},
issn = {1738-3684},
support = {//Korean Association for Geriatric Psychiatry/ ; RS-2024-00450828//National Research Foundation of Korea/ ; //Ministry of Science and ICT/ ; },
abstract = {OBJECTIVE: This review overviewed the recent paradigm shifts in the diagnosis and management of Alzheimer's disease (AD), emphasizing the 2024 Alzheimer's Association (AA) revised criteria, advances in cerebrospinal fluid (CSF) and blood-based biomarkers (BBMs), and practical considerations for anti-amyloid monoclonal antibody therapy.

METHODS: We conducted a narrative appraisal of consensus frameworks (2018 National Institute on Aging-Alzheimer's Association [NIA-AA] amyloid, tau, and neurodegeneration [AT(N)] and the 2024 AA criteria), clinical practice guidance from AA released in 2025, regulatory status of CSF and BBMs. Intended-use settings (triage vs. confirmatory) of BBMs and implementation of anti-amyloid anti-body treatments (lecanemab or donanemab) in real-world practice in Korea were also reviewed.

RESULTS: The 2024 AA criteria define AD biologically and designate A and T as core biomarkers; Core 1 biomarkers can establish AD irrespective of symptoms, whereas Core 2 biomarkers refine staging. A two-cutoff BBM strategy (positive/intermediate/negative) reduces misclassification and guides confirmatory CSF/positron emission tomography (PET) or retesting. BBMs now approach CSF/PET accuracy for amyloid detection, enable triage and, in selected settings, confirmation, and show utility for monitoring treatment response. Integration of clinical stages (1-6) with biological stages (A-D) clarifies syndrome-pathology discordance. Special scenarios-maintenance after induction, APOE ε4 homozygotes, Down syndrome, and serious mental illness-require individualized risk-benefit assessment. In South Korea, constrained access to tau PET and some BBMs necessitates Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision-anchored evaluation with selective biomarker testing.

CONCLUSION: Biomarker-oriented diagnosis and anti-amyloid therapies are reshaping AD care. Priorities include rigorous validation of BBMs across populations, equitable access to core biomarkers, safety strategies, and real-world evidence to implement maintenance and special-population care pathways.},
}

@article {pmid41678018,
year = {2026},
author = {Arbaciauskaite, S and Silvestri, S and Luo, P and Krüger, C and Mossmann, ZJ and Allelein, S and Scholz, A and Loeffler, D and Fiorenza, S and Menale, A and Torino, E and Kuhlmeier, D and Peters, O and Lehnardt, S},
title = {Microglia-Derived Extracellular Vesicles from Alzheimer's Disease Patients Carry miRNAs Driving a Neuroinflammatory Response.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {435},
pmid = {41678018},
issn = {1559-1182},
support = {LE 2420/7-1, SFB-TRR167/B03//Deutsche Forschungsgemeinschaft/ ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/genetics/cerebrospinal fluid/pathology/metabolism ; *Extracellular Vesicles/metabolism ; Humans ; *MicroRNAs/metabolism/genetics ; Animals ; Mice ; *Neuroinflammatory Diseases/genetics/pathology/metabolism ; Aged ; Male ; Female ; HEK293 Cells ; Aged, 80 and over ; },
abstract = {Alzheimer's disease (AD) represents the most common cause of dementia and urgently requires sensitive biomarkers and effective therapies. Extracellular vesicles represent membranous nano-sized particles secreted from cells, which serve as intercellular messengers participating in central nervous system (CNS) homeostasis, but also are implicated in AD pathogenesis. In addition, EVs containing disease-specific signatures, such as microRNAs (miRNAs), are considered as potent tools for the diagnosis and treatment of AD and other brain disorders. In this study, we used TMEM119 antibody to immunocapture microglia-derived EVs from cerebrospinal fluid (CSF) of AD patients and control subjects. EVs harvested from these CSF samples contained distinct disease-specific miRNA profiles, as assessed by small RNA sequencing. Using a HEK TLR reporter cell system, we found that these miRNA are potent activators of human TLR8, an established RNA sensor. Out of the miRNAs present in AD-associated EVs, selected oligonucleotides were synthesized and loaded into BV2 microglia-derived EVs. Exposure of primary murine microglia to these miRNA-loaded EVs led to TNF release from these cells, thereby driving a neuroinflammatory response. Taken together, putatively microglia-derived EVs from the CSF of AD patients contain miRNAs, which are capable of activating hTLR8 and inducing an inflammatory response from microglia.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/genetics/cerebrospinal fluid/pathology/metabolism
*Extracellular Vesicles/metabolism
Humans
*MicroRNAs/metabolism/genetics
Animals
Mice
*Neuroinflammatory Diseases/genetics/pathology/metabolism
Aged
Male
Female
HEK293 Cells
Aged, 80 and over

@article {pmid41677765,
year = {2026},
author = {Kim, H and Hong, JY and Yeo, C and Kim, H and Jeon, WJ and Lee, J and Lee, YJ and Ha, IH},
title = {Neuroprotective Effects of Herbal Formula Yookgong-Dan on Oxidative Stress-Induced Tau Hyperphosphorylation in Rat Primary Hippocampal Neurons.},
journal = {Biology},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/biology15030294},
pmid = {41677765},
issn = {2079-7737},
abstract = {This study sought to evaluate the neuroprotective effects of YGD in an oxidative stress-induced Alzheimer's disease (AD)-like cellular model and to elucidate the underlying molecular pathways, with a focus on tau phosphorylation, Aβ accumulation, and antioxidant defense mechanisms. Rat primary hippocampal neurons were exposed to hydrogen peroxide to induce oxidative stress. The effects of YGD on neuronal viability, neurite outgrowth, and synaptic integrity were assessed using the immunodetection of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD-95), and synapsin-1. Levels of phosphorylated tau and Aβ were quantified, and the involvement of extracellular signal-regulated kinase (ERK), glycogen synthase kinase 3β (GSK3β), and nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways was examined. Additionally, in silico molecular docking studies targeting the ATP-binding site of GSK3β were conducted to screen major phytochemicals from the ten medicinal herbs constituting YGD. YGD markedly enhanced neuronal viability under oxidative stress, promoted neurite extension, and increased synaptic marker expression (MAP2, PSD-95, and synapsin-1). Treatment reduced phosphorylated tau by suppressing ERK and GSK3β activation and significantly decreased Aβ accumulation. YGD also upregulated antioxidant defenses via the activation of the Nrf2 pathway. Docking simulations identified oleanolic acid (from Cornus officinalis) as the most potent GSK3β binder (-9.86 ± 0.40 kcal/mol), forming stable interactions with ARG96, ASN95, and GLU97. Additional compounds, including alisol C, drypemolundein B, and friedelin, demonstrated favorable binding energies and engaged key ATP-binding site residues. YGD confers neuroprotection through the integrated modulation of tau phosphorylation, Aβ pathology, and oxidative stress, partly via the multi-target engagement of GSK3β by its constituent phytochemicals. These findings support that YGD attenuates oxidative stress-induced AD-like cellular alterations.},
}

@article {pmid41677657,
year = {2026},
author = {Dagla, I and Gkikas, F and Gikas, E and Tsarbopoulos, A},
title = {Targeting Amyloid Beta Aggregation and Neuroinflammation in Alzheimer's Disease: Advances and Future Directions.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030295},
pmid = {41677657},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Neuroinflammatory Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems ; *Protein Aggregation, Pathological/drug therapy ; Neuroprotective Agents/therapeutic use/pharmacology ; *Protein Aggregates/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Among the diverse pathological features of AD, amyloid beta (Aβ) aggregation and neuroinflammation are recognized as central and interlinked mechanisms driving disease progression. This review focuses specifically on these two processes and highlights current pharmacological limitations in modifying disease pathology. Natural products such as curcumin, resveratrol, Ginkgo biloba, epigallocatechin gallate (EGCG), crocin, ashwagandha, and cannabidiol (CBD) have shown promising activity in modulating Aβ aggregation and neuroinflammatory pathways, offering multi-target neuroprotective effects in preclinical studies. However, their therapeutic application remains hindered by poor solubility, instability, rapid metabolism, and limited blood-brain barrier (BBB) permeability. To overcome these barriers, nanotechnology-based drug delivery systems-including polymeric nanoparticles, niosomes, solid lipid nanoparticles, and chitosan-based carriers-have emerged as effective strategies to enhance brain targeting, bioavailability, and pharmacological efficacy. We summarize the mechanistic insights and nanomedicine approaches related to these bioactives and discuss their potential in developing future disease-modifying therapies. By focusing on Aβ aggregation and neuroinflammation, this review provides a targeted perspective on the evolving role of natural compounds and nanocarriers in AD treatment.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
*Neuroinflammatory Diseases/drug therapy
Blood-Brain Barrier/metabolism
Drug Delivery Systems
*Protein Aggregation, Pathological/drug therapy
Neuroprotective Agents/therapeutic use/pharmacology
*Protein Aggregates/drug effects

@article {pmid41677635,
year = {2026},
author = {Acquarone, E and Roy, SM and Staniszewski, A and Watterson, DM and Arancio, O},
title = {The Highly Selective 5-HT2B Receptor Antagonist MW073 Mitigates Aggressive Behavior in an Alzheimer's Disease Mouse Model.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/cells15030273},
pmid = {41677635},
issn = {2073-4409},
support = {AG066722/GF/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Aggression/drug effects ; Disease Models, Animal ; Mice ; *Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use ; Male ; Mice, Transgenic ; *Receptor, Serotonin, 5-HT2B/metabolism ; *Behavior, Animal/drug effects ; *Fluorobenzenes/pharmacology/therapeutic use ; Humans ; Mice, Inbred C57BL ; },
abstract = {Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40-60% of patients and represent a major source of caregiver burden. Serotonin 5-HT2B receptor levels are increased in the AD patient brain, and thus, treatment of AD animal models with the selective 5-HT2B receptor antagonist MW073 in prevention or disease stage paradigms attenuates Aβ- or tau-induced dysfunction. Methods: We investigated the effects of MW073 treatment on the aggressive behavior of Tg2576 mice in a resident-intruder assay. Results: MW073 treatment significantly reduced aggressive behavior in male Tg2576 mice. Conclusions: MW073 efficacy in treating aggression in Tg2576 mice implicates 5-HT2B receptor-mediated signaling in AD neuropsychiatric symptoms as well as cognitive and behavioral dysfunction.},
}

Animals
*Alzheimer Disease/drug therapy
*Aggression/drug effects
Disease Models, Animal
Mice
*Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use
Male
Mice, Transgenic
*Receptor, Serotonin, 5-HT2B/metabolism
*Behavior, Animal/drug effects
*Fluorobenzenes/pharmacology/therapeutic use
Humans
Mice, Inbred C57BL

@article {pmid41677117,
year = {2026},
author = {Li, Y and Cheng, Q and Tian, S and Li, X and Chen, Y and Guo, Y and Jiang, Y and Tao, Y and Niu, X and Hu, H and Liu, Y and Li, S},
title = {Oridonin Ameliorates Alzheimer's Disease-Like Pathology in Male Mice Through Inhibition of Receptor-Interacting Protein Kinase 1.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70185},
pmid = {41677117},
issn = {1099-1573},
support = {82404605//National Natural Science Foundation of China/ ; U23A20510//National Natural Science Foundation of China/ ; U24A20806//National Natural Science Foundation of China/ ; 32300318//National Natural Science Foundation of China/ ; BX20220048//National Postdoctoral Program for Innovative Talents/ ; 2022MD723713//China Postdoctoral Science Foundation/ ; 2022NSFSC1362//Natural Science Foundation of Sichuan Province/ ; 2023ZYD0051//Natural Science Foundation of Sichuan Province/ ; 2024NSFSC1324//Natural Science Foundation of Sichuan Province/ ; },
abstract = {Oridonin (Ori) is a bioactive diterpenoid from Rabdosia rubescens that exhibits potent anti-inflammatory and neuroprotective properties. However, its potential role in Alzheimer's disease (AD), especially in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains unclear. This study aimed to investigate Ori's therapeutic mechanism in AD by targeting RIPK1. We utilized cellular thermal shift assay (CETSA), drug affinity responsive target stability assay (DARTS), and bio-layer interferometry (BLI) to verify the binding of Ori to RIPK1. In vitro, inflammatory and necroptotic responses were assessed in BV2 microglial cells and HT22 neuronal cells using enzyme-linked immunosorbent assay (ELISA), reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, immunofluorescence, and flow cytometry assays. In vivo, we evaluated Ori's therapeutic efficacy in 5× FAD transgenic mice, a well-established AD model, through behavioral analysis using the Morris water maze, along with histological and biochemical assessments of brain tissues. Ori demonstrated a robust interaction with RIPK1 (KD = 533 nM) and significantly increased its thermal and proteolytic stability. Treatment with Ori markedly suppressed the secretion of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) in microglia by inhibiting the RIPK1-ERK1/2-NF-κB signaling pathway. In neurons, Ori effectively blocked the activation of the RIPK1-RIPK3-MLKL signaling cascade, prevented necrosome formation, and significantly reduced necroptotic cell death. Importantly, in the 5× FAD mouse model, Ori treatment substantially improved spatial learning and memory performance, decreased amyloid-beta (Aβ) plaque deposition, and attenuated inflammatory and necroptotic markers in both cortical and hippocampal regions. Ori as a natural small-molecule inhibitor of RIPK1, capable of concurrently mitigating neuroinflammation and necroptosis-two critical pathological processes underpinning AD. These findings strongly support Ori's potential as a disease-modifying therapeutic for AD.},
}

@article {pmid41676727,
year = {2026},
author = {Tong, M and Mehfooz, F and Zhang, S and Wang, Y and Fang, S and Saykin, AJ and Wang, X and Yan, J and , },
title = {Learning a Continuous Progression Trajectory of Amyloid in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.03.703568},
pmid = {41676727},
issn = {2692-8205},
abstract = {BACKGROUND: Understanding of Alzheimer progression is critical for timely diagnosis and treatment evaluation, but traditional discrete diagnostic groups often lack sensitivity to subtle early-stage changes.

METHODS: We developed SLOPE, an unsupervised dimensionality reduction method that models the amyloid progression in AD on a continuous scale while preserving the temporal order of longitudinal follow-up visits. Applied to longitudinal amyloid PET data, SLOPE generated a two-dimensional trajectory capturing global amyloid accumulation across the AD continuum.

RESULTS: SLOPE-derived staging scores better preserved temporal progression across diagnostic groups and longitudinal follow-up visits and can be generalized to held-out subjects. The learned trajectory revealed biologically consistent amyloid spreading patterns and greater sensitivity to early progression than global amyloid SUVR.

DISCUSSION: SLOPE provides a continuous staging of amyloid pathology that complements global amyloid measures by capturing early localized progression. These properties highlight its potential in disease modeling and monitoring, particularly in early and preclinical stages of AD.},
}

@article {pmid41676487,
year = {2026},
author = {Tagmazian, AA and Schwarz, C and Lange, C and Pitkänen, E and Vuoksimaa, E and , },
title = {petVAE: A Data-Driven Model for Identifying Amyloid PET Subgroups Across the Alzheimer's Disease Continuum.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.02.703218},
pmid = {41676487},
issn = {2692-8205},
abstract = {Amyloid-β (Aβ) PET imaging is a core biomarker and is considered sufficient for the biological diagnosis of Alzheimer's disease (AD). However, it is typically reduced to a binary Aβ™/Aβ+ classification. In this study, we aimed to identify subgroups along the continuum of Aβ accumulation including subgroups within Aβ- and Aβ+. We used a total of 3,110 of Aβ PET scans from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) datasets to develop petVAE , a 2D variational autoencoder model. The model accurately reconstructed Aβ PET scans without prior labeling or pre-selection based on scanner type or region of interest. Latent representations of scans extracted from the petVAE (11,648 latent features per scan) were used to visualize, analyze, and cluster the AD continuum. We identified the latent features most representative of the continuum, and clustering of PET scans using these features produced four clusters. Post-hoc characterization revealed that two clusters (Aβ-, Aβ-+) were predominantly Aβ negative and two (Aβ+, Aβ++) were predominantly Aβ positive. All clusters differed significantly in standardized uptake value ratio (p < 1.64×10 [-8]) and cerebrospinal fluid (CSF) Aβ (p < 0.02), demonstrating petVAE's ability to assign scans along the Aβ continuum. The clusters at the extremes of the continuum (Aβ-, Aβ++) resembled to the conventional Aβ negative and Aβ positive groups and differed significantly in cognitive performance, Apolipoprotein E (APOE) ε4 prevalence, and Aβ, tau and phosphorylated tau CSF biomarkers (p < 3×10 [-6]). The two intermediate clusters (Aβ-+, Aβ+) showed significantly higher odds of carrying at least one APOE ε4 allele compared with the Aβ-cluster (p < 0.026). Participants in Aβ+ or Aβ++ clusters exhibited a significantly faster rate of progression to AD compared to Aβ-group (Hazard ratio = 2.42 and 9.43 for groups Aβ+ and Aβ++, respectively, p < 1.17×10 [-7]). Thus, petVAE was capable of reconstructing PET scans while also extracting latent features that effectively represented the AD continuum and defined biologically meaningful clusters. By capturing subtle Aβ-related changes in brain PET scans, petVAE -based classification enables the detection of preclinical AD stages and offers a new data-driven framework for studying disease progression.},
}

@article {pmid41676474,
year = {2026},
author = {Rossitto, LM and Foo, J and Di Silvestri, JM and Lehmann, L and Brunelli, M and Nie, Y and Muñoz-Mayorga, D and Xiao, Q and Dai-Liu, AY and Jati, S and Rossi, M and Daneman, R and Kelly, JW and Newman, JC and Myers, SA and Chen, X},
title = {Ketone body β-hydroxybutyrate restores neuronal Tau proteostasis via ketolysis-independent mechanism.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.30.702936},
pmid = {41676474},
issn = {2692-8205},
abstract = {Metabolic interventions that induce ketosis, including ketogenic diets, caloric restriction, intermittent fasting, and exercise, show promise in the treatment of Alzheimer's disease (AD) and related tauopathies. β-hydroxybutyrate (βHB), the primary ketone body produced during ketosis, reproduces key features of these metabolic interventions, but the molecular mechanism underlying its neuroprotective properties is not fully understood. Here, we demonstrate that a βHB precursor diet is sufficient to ameliorate Tau pathophysiology in a tauopathy mouse model. Furthermore, across in vitro , ex vivo , and in vivo models, we find that βHB enhances neuronal Tau proteostasis and reduces Tau aggregation and secretion. Importantly, these effects are independent of βHB's oxidation for ATP production, as its ketolysis-resistant enantiomer reproduces these benefits, indicating that ketolysis is dispensable for these effects. Overall, these data position βHB as a novel therapeutic avenue for AD and tauopathy and elucidate a novel mechanism of action of metabolic interventions in neurodegenerative disease.},
}

@article {pmid41676156,
year = {2026},
author = {Weng, Y and He, T and Li, M and Zhou, Q and Xie, J and Wei, L and Wang, X and Wang, JZ and Zhong, M and Li, S},
title = {Microglial histone H3K18 crotonylation promotes STAT1 expression and induces cognitive deficit in Alzheimer disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1744375},
pmid = {41676156},
issn = {1664-3224},
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics ; *Histones/metabolism ; Mice ; *Microglia/metabolism ; *STAT1 Transcription Factor/metabolism/genetics ; *Cognitive Dysfunction/metabolism/etiology ; Disease Models, Animal ; Hippocampus/metabolism ; Male ; Protein Processing, Post-Translational ; Mice, Transgenic ; Amyloid beta-Peptides ; Humans ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet the epigenetic mechanisms underlying its pathogenesis remain incompletely understood. Histone crotonylation, a novel post-translational modification, has been implicated in neuroinflammation. However, its role in AD-related cognitive impairment has not been elucidated.

METHODS: Histone crotonylation was examined in 5xFAD and Aβ42-injected mice. Crotonic acid was administered intracerebroventricular (ICV) to elevate hippocampal histone crotonylation in wild-type mice. Cognitive function was assessed using behavioral tests. Synaptic integrity was evaluated via western blotting and Golgi staining. Microglial activation and co-localization of H3K18cr were determined by immunofluorescence. Transcriptomic analysis identified differentially expressed genes and enriched pathways. The role of signal transducer and activator of transcription 1 (STAT1) was validated in BV2 microglial cells using the STAT1 inhibitor fludarabine.

RESULTS: Hippocampal pan-histone H3 crotonylation (H3Kcr) and H3K18cr were significantly upregulated in both 5xFAD and Aβ42-injected mice compared to controls. ICV injection of crotonic acid markedly elevated hippocampal H3Kcr and H3K18cr levels and induced significant cognitive deficits, shown by impaired novel object recognition and fear conditioning performance. Crotonic acid treatment resulted in synaptic dysfunction, including reduced synaptic markers (SYN1, SYT, GluA2, GluN2B) and decreased CA1 dendritic spine density. Crotonic acid also induced microgliosis with elevated Iba1 expression. H3K18cr was specifically upregulated in microglia, with no significant changes observed in neurons or astrocytes. Transcriptomic analysis identified 478 differentially expressed genes enriched predominantly in immune-related pathways, with STAT1 highlighted as a key upstream transcription factor. In BV2 cells, crotonic acid significantly increased total and phosphorylated STAT1 (Tyr701) levels via a JAK1-independent mechanism. Treatment with fludarabine effectively suppressed STAT1 expression and attenuated the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β.

CONCLUSION: This study provides the first evidence that elevated microglial H3K18cr contributes to AD-related cognitive impairment by promoting STAT1 expression and subsequent neuroinflammation. These findings identify microglial histone crotonylation as a novel epigenetic mechanism in AD pathogenesis and suggest that targeting the H3K18cr-STAT1 axis may represent a potential therapeutic strategy for AD.},
}

Animals
*Alzheimer Disease/metabolism/genetics
*Histones/metabolism
Mice
*Microglia/metabolism
*STAT1 Transcription Factor/metabolism/genetics
*Cognitive Dysfunction/metabolism/etiology
Disease Models, Animal
Hippocampus/metabolism
Male
Protein Processing, Post-Translational
Mice, Transgenic
Amyloid beta-Peptides
Humans

@article {pmid41675725,
year = {2026},
author = {Patel, T and Henna, F and Sharif, I and Javed, I and Mustafa, F and Sharif, H and Nasir, F and Javaid, M and Usman, SF and Hanani, C and Anand, N},
title = {A narrative review on the therapeutic potential of stem cells in neurodegenerative diseases: advances, insights, and challenges.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {2},
pages = {1441-1453},
pmid = {41675725},
issn = {2049-0801},
abstract = {BACKGROUND: Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

OBJECTIVES: This narrative review aims to appraise the treatment potential of various stem cell types in managing NDs, highlighting their functional pathways, delivery methods, and current experimental validation.

METHODS: A comprehensive literature search was carried out based on data retrieved from PubMed, The Cochrane Library, and ClinicalTrials.gov. Thirty-one studies that fulfill PICO criteria and only English-language publications are incorporated in this review. No part of the study design, data collection, analysis, or interpretation was conducted using artificial intelligence.

RESULTS: Stem cells, including embryonic stem cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells, and neural stem cells, possess distinctive regenerative properties. MSC-derived exosomes can traverse the blood-brain barrier and improve nerve cell longevity. Administration routes such as intravenous, intranasal, and direct brain transplantation are being studied. Neurodegenerative conditions such as PD, AD, HD, and ALS have been widely studied for therapeutic benefits.

CONCLUSION: Regardless of their potential, stem cell therapies raise health risks, including neoplastic growth and immunological incompatibility, alongside bioethical issues. Developments in genetic modification, nanotechnology, and preconditioning strategies are being analyzed to optimize outcomes. Long-term research, harmonization of protocols, and extended patient follow-up are essential for the safe and effective development of medical applications.},
}

@article {pmid41675591,
year = {2026},
author = {Malliou, G and Reus, LM and Pijnenburg, YAL and van der Flier, WM and de Wit, NM and Chornyi, S and Kooij, G and de Vries, HE and Teunissen, CE and Visser, PJ and Ophoff, RA and Tijms, BM},
title = {Distinct CSF lipidomic profiles are associated with five proteomic subtypes in patients with Alzheimer's disease.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {11},
pmid = {41675591},
issn = {3059-4944},
abstract = {BACKGROUND: Alzheimer's disease (AD) is molecularly heterogeneous. In our previous cerebrospinal fluid (CSF) proteomic study in AD, we identified and validated five distinct molecular subtypes characterized by neuronal hyperplasticity (subtype 1), innate immune activation (subtype 2), RNA dysregulation (subtype 3), choroid plexus dysfunction (subtype 4) and blood-brain barrier impairment (subtype 5). These subtypes also differed in the CSF levels of proteins involved in lipid metabolism, suggesting that lipid dysregulation in AD might be subtype specific.

METHODS: We performed untargeted lipidomics on CSF samples from 601 individuals in the Amsterdam Dementia Cohort who were previously included in our proteomic study (n = 416 AD, 185 controls). Using the CSH-QTOF platform for complex lipids, 3,532 lipids were detected in CSF, 270 of which could be mapped to 13 different lipid classes. Lipid levels were compared between each AD subtype and controls using linear regression models adjusted for age and sex (R v4.2.1). Lipids with significantly different levels (p < 0.05) were included for pathway enrichment analysis with MetaboAnalyst6.0.

RESULTS: We observed alterations in the levels of 1,893 lipids, with the majority associated with a single AD subtype. Subtype 3 (RNA dysregulation) exhibited the most pronounced alterations, with altered CSF levels of 669 lipids, including triglycerides and fatty acids, which were reduced compared to controls. Subtype 4 (choroid plexus dysfunction) and subtype 5 (blood-brain barrier dysfunction) both had alterations in the same set of 150 lipids, but with changes occurring in opposite directions (i.e., decreased in subtype 4, and increased in subtype 5). These lipids were associated with sphingolipid metabolism and lipid transport. Subtype 1 (neuronal hyperplasticity) and subtype 2 (innate immune activation) had less pronounced differences compared to the other subtypes. Subtype 1 had increased levels of several phospholipids, indicating neuronal membrane remodeling, and subtype 2 decreased arachidonic acid levels, a precursor of immunoregulatory oxylipins.

CONCLUSION: Our findings reveal subtype-specific lipid metabolism alterations in AD. Currently, five lipid-targeting drugs are in phase 1 and 2 trials. Our results suggest that treatment efficacy may vary by subtype. Understanding these molecular differences can inform trial design and analysis, advancing the development of tailored therapies for AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-026-00018-z.},
}

@article {pmid41618453,
year = {2026},
author = {Swain, A and Soni, ND and Gaspar, RB and Davis, JG and Liu, F and Juul, H and Nanga, RPR and Baur, JA and Reddy, R},
title = {In vivo imaging of glutamate uncovers the neuroprotective effects of nicotinamide riboside on excitotoxicity in an Alzheimer's mouse model.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {37},
pmid = {41618453},
issn = {1758-9193},
support = {R01 DK098656/DK/NIDDK NIH HHS/United States ; R01 AG063869/AG/NIA NIH HHS/United States ; P41 EB029460/EB/NIBIB NIH HHS/United States ; R01 DK098656/DK/NIDDK NIH HHS/United States ; R01 AG063869/AG/NIA NIH HHS/United States ; P41 EB029460/EB/NIBIB NIH HHS/United States ; },
abstract = {BACKGROUND: Nicotinamide adenine dinucleotide (NAD[+]) precursors, such as nicotinamide riboside (NR), have gained interest as potential therapeutics for alleviating Alzheimer’s disease (AD) pathology. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can provide insights into the effects of NR on AD by virtue of its sensitivity to monitoring the metabolic status of tissue in vivo.

METHODS: This study used glutamate-weighted CEST (GluCEST) MRI to monitor glutamate-associated metabolic changes following NR treatment in the 5xFAD mouse model of AD. Drinking water was supplemented with NR or provided as is to animals over the course of expected disease progression prior to imaging experiments. Following imaging, an immunohistochemical assay to monitor the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) was performed to assess the extent of neuroinflammatory glial responses. A two-way ANCOVA with interaction was performed for statistical analysis of both CEST and IHC data.

RESULTS: Results from GluCEST revealed significantly higher glutamate levels in the hippocampal dentate gyrus of AD mice compared to WT, with a significant reduction following treatment. GFAP staining mirrored this trend, implicating reactive astrogliosis as a mechanism for elevated glutamate. Similar patterns were observed in the cerebral peduncles, a white matter bundle, in which GFAP and Iba1 supported GluCEST findings and suggested neuroinflammation in axonal tracts. Our findings are in concordance with studies reporting elevated glutamate associated with reactive gliosis and morphological changes disrupting glutamate imbalance. Interestingly, NR restores glutamate homeostasis and alleviates neuroinflammatory processes, thus rescuing tissue from excitotoxic insults.

CONCLUSION: Overall, this study demonstrates the potential of NR to mitigate glutamate-driven excitotoxicity in AD pathology, and highlights GluCEST as a sensitive in vivo, clinically translatable biomarker for neuroinflammation and excitotoxicity.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01958-0.},
}

@article {pmid41673679,
year = {2026},
author = {Liao, J and Mou, H and Luo, S and Shen, L and Jiao, B},
title = {Microbiota and Alzheimer's disease: mechanistic insights from a multi-organ perspective.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {3},
pmid = {41673679},
issn = {2047-9158},
support = {82371434//National Natural Science Foundation of China/ ; 2024JJ2097//Outstanding Youth Fund of Hunan Provincial Natural Science Foundation/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by multifactorial mechanisms. Increasing evidence suggests that dysbiosis, a term denoting an imbalance in the composition of the microbiota, may play a pivotal role in the pathogenesis of AD across multiple bodily sites, including the gut, oral cavity, nasal passages, lungs, and skin. Microbial imbalances may promote neuroinflammation, immune dysfunction, and metabolic disturbances through complex host-microbiota networks. This review synthesizes current advances in the understanding of microbiota-driven modulation of AD, introduces the "Multi-Axis Co-Regulation" concept, and evaluates microbial biomarkers for early diagnosis. Finally, the translational potential of microbiota-targeting interventions, including probiotics, dietary modulation, fecal microbiota transplantation, and oral microbiome-based therapies, are discussed, which represent novel strategies for precision prevention and treatment of AD.},
}

@article {pmid41673254,
year = {2026},
author = {Nazli, D and Ipekgil, D and Poyraz, YK and Can, K and Okmen, I and Turhanlar-Sahin, E and Sert Serdar, B and Kocturk, S and Ozhan, G},
title = {Epigallocatechin Gallate and Punicalagin Combination Reduces Aβ Aggregation and Promotes Neurogenesis in Adult Zebrafish Brain.},
journal = {Journal of neuroscience research},
volume = {104},
number = {2},
pages = {e70119},
doi = {10.1002/jnr.70119},
pmid = {41673254},
issn = {1097-4547},
support = {2021.KB.SAG.018//Dokuz Eylül Üniversitesi/ ; 121Z900//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; IG 3024//European Molecular Biology Organization/ ; },
mesh = {Animals ; Zebrafish ; *Catechin/analogs & derivatives/pharmacology/administration & dosage ; *Hydrolyzable Tannins/pharmacology/administration & dosage ; *Amyloid beta-Peptides/metabolism ; *Neurogenesis/drug effects ; *Brain/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/administration & dosage ; Alzheimer Disease/metabolism/drug therapy ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral alterations. The pathogenesis of AD involves the accumulation of amyloid-beta (Aβ) plaques and the hyperphosphorylated tau proteins, which disrupt neuronal function and trigger neuroinflammation. This study explores the therapeutic potential of epigallocatechin gallate (EGCG) and punicalagin (PU) in mitigating Aβ-induced toxicity using an adult zebrafish model of AD. Our results demonstrate that the EGCG + PU combination significantly reduces Aβ accumulation, protects against cellular damage, suppresses acetylcholinesterase (AChE) activity, and normalizes the expression of amyloidogenic and AD-related genes. Additionally, EGCG + PU treatment alleviates neuroinflammation by suppressing glial activation, including reductions in L-plastin and proinflammatory cytokine expression, while promoting neuronal recovery through mechanisms of neurogenesis and neuroprotection. Notably, the combination treatment restored neuronal density and improved behavioral outcomes by alleviating anxiety- and aggression-like behaviors associated with Aβ toxicity. These results underscore the synergistic neuroprotective effects of EGCG + PU, highlighting their potential as a novel therapeutic approach for mitigating the pathological, behavioral, and inflammatory aspects of AD.},
}

Animals
Zebrafish
*Catechin/analogs & derivatives/pharmacology/administration & dosage
*Hydrolyzable Tannins/pharmacology/administration & dosage
*Amyloid beta-Peptides/metabolism
*Neurogenesis/drug effects
*Brain/drug effects/metabolism
*Neuroprotective Agents/pharmacology/administration & dosage
Alzheimer Disease/metabolism/drug therapy
Disease Models, Animal

@article {pmid41672403,
year = {2026},
author = {Fenton, L and Aslanyan, V and Jacobs, DM and Salmon, DP and Brewer, JB and Rissman, RA and Shadyab, AH and Harrison, TM and Evans, AC and LaCroix, AZ and Feldman, HH and Baker, LD and Pa, J},
title = {Relationships between fine memory discrimination and tau burden in two independent cohorts of older adults.},
journal = {Neuropsychologia},
volume = {},
number = {},
pages = {109393},
doi = {10.1016/j.neuropsychologia.2026.109393},
pmid = {41672403},
issn = {1873-3514},
abstract = {Cognitive assessments sensitive to the integrity of the medial temporal lobe, an area vulnerable to early tau deposition, may serve as low-cost adjunctive markers of underlying tau pathology in older adults. The Mnemonic Similarity Task (MST) is a fine memory discrimination task designed to assess hippocampal integrity. The current cross-sectional study utilized baseline data from two AD prevention trials (the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study and the Exercise in Adults with Mild Memory Problems (EXERT) trial) to examine relationships between MST performance, amyloid-beta, tau, and hippocampal volume. We additionally explored relationships between performance on a traditional memory test, Logical Memory, and AD-related brain measures. Poorer fine memory discrimination was associated with higher tau as assessed by PET in A4 (N=407, 59% female, mean age=71.66, age range=65-85) and CSF (p-tau181, total tau) in EXERT (N=41, 61% female, mean age=74.10, age range=65-89). Poorer fine memory discrimination was also associated with higher amyloid PET in A4 and smaller hippocampal volume in EXERT. Poorer delayed recall on Logical Memory was associated with higher tau and amyloid burden in A4 and with lower hippocampal volume in EXERT. Poorer retention on Logical Memory was associated with higher tau in Braak I and amyloid in A4 and with CSF tau and lower hippocampal volume in EXERT. These results support the potential of fine memory discrimination as measured by the MST as an adjunctive, accessible screening measure associated with higher tau in cognitively normal, amyloid positive older adults and older adults with amnestic MCI.},
}

@article {pmid41672382,
year = {2026},
author = {Khan, S and Imam, A and Singh, S and Ahmed, A and Hassan, MI and Shahid, M and Athar, F and Islam, A},
title = {Exploring the intersection of Alzheimer's disease and comorbidities: a review of the interplay between multiple chronic conditions.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {168190},
doi = {10.1016/j.bbadis.2026.168190},
pmid = {41672382},
issn = {1879-260X},
abstract = {Alzheimer's disease (AD) represents degenerative brain disorder that impairs both cognitive functions and daily living activities gradually. It is frequently linked with other disorders such as psychosis, cardiovascular disorders, diabetes, and depression, all of which may influence the disease's onset, trajectory, and treatment approaches. These comorbidities can affect the onset, progression, and management of AD. This review focuses to explore the interplay of AD and comorbidities, and to examine the interplay between multiple chronic conditions. The review found that AD and comorbidities have a complex and bidirectional relationship. Comorbidities can affect the onset, progression, and management of AD, and AD can also affect the management and outcomes of comorbidities. The review also found that comorbidities may have an impact on caregiver burden, healthcare utilization and mortality. The findings suggest that the management of AD should take into account the presence and management of comorbidities to improve the overall outcomes for patients with AD. The literature also suggests that the management of comorbidities should be integrated in the management of AD patients. Furthermore, the review highlights the critical role of timely detection and treatment of comorbidities in AD patients to delay onset and mitigate disease progression. Additionally, it is crucial to consider the influence of comorbidities when selecting treatment options and the management of side effects and adverse events in AD patients. The literature reviewed in this article suggests that a multidisciplinary approach is needed in managing AD patients with comorbidities, which includes regular screening, early detection, and management of comorbidities in addition to managing AD.},
}

@article {pmid41672293,
year = {2026},
author = {Ge, Y and Weng, Y and Chen, Y},
title = {Elucidating the toxicological impact and mechanism of plasticizers exposure on Alzheimer's disease through network toxicology and molecular docking.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {116005},
doi = {10.1016/j.fct.2026.116005},
pmid = {41672293},
issn = {1873-6351},
abstract = {This study aimed to explore the underlying mechanisms and key targets of widely used plasticizers, including dimethyl phthalate (DMP), diethyl phthalate (DEP), and dioctyl phthalate (DOP), to the pathogenesis of Alzheimer's disease (AD). Network toxicology, molecular docking, and dynamics simulation screened candidate targets for plasticizer in increasing AD risk. Three machine learning algorithms and two microarray datasets identified key targets, whose immune relevance was assessed by CIBERSORT. An Aβ42-induced BV2 microglia model validated their role. We identified 83 plasticizer targets relevant to AD, which were enriched in KEGG pathways like apoptosis and neuroactive ligand-receptor interaction. CDK5, SLC2A1, and STAT3 were confirmed as key targets, showing consistent differential expression in two AD datasets. Their expression correlated with M1 macrophage infiltration. Molecular docking and dynamics simulations demonstrated that plasticizers stably bind these targets with high affinity. In Aβ42-induced BV2 microglia, phthalate treatment elevated inflammatory factors (TNF-α, IL-1β, IL-6) and STAT3 expression. This study demonstrated the possible mechanistic associations between plasticizers exposure and AD, and STAT3 might be key target of plasticizers.},
}

@article {pmid41672268,
year = {2026},
author = {de Melo Silva, JG and de Medeiros Barros, W and Lopes, NMCP and Bellozi, PMQ},
title = {Alzheimer's disease: Current therapeutic strategies and emerging perspectives for multifactorial intervention.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111640},
doi = {10.1016/j.pnpbp.2026.111640},
pmid = {41672268},
issn = {1878-4216},
abstract = {Alzheimer's Disease (AD) is a progressive, multifactorial neurodegenerative condition and the most common form of dementia, affecting millions globally. Its incidence increases with age and is characterized by cognitive decline, functional impairments, and behavioral disturbances. Although its etiology remains unclear, AD is believed to result from a complex interaction between genetic, environmental, and lifestyle factors. Several hypotheses have been proposed to explain its pathogenesis, including the amyloid cascade, tau neurofibrillary tangle formation, cholinergic and glutamatergic dysfunctions, and, more recently, lipid invasion. Current treatment strategies involve both pharmacological and non-pharmacological interventions. In Brazil, acetylcholinesterase inhibitors and memantine are widely used. Recently, efforts have focused on developing new therapies, such as monoclonal antibodies, with three representatives already approved by the FDA, in addition to innovative approaches such as the use of technology and virtual reality for cognitive therapies. However, there is still a need for research that enables early diagnosis, interventions with fewer adverse effects, and the development of therapies targeting multiple mechanisms. Therefore, the pursuit of more effective and personalized treatments is essential to mitigate the societal impacts of AD.},
}

@article {pmid41672134,
year = {2026},
author = {Maneu, V and García, AG},
title = {P2X7 receptors as targets for neuroprotection.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110877},
doi = {10.1016/j.neuropharm.2026.110877},
pmid = {41672134},
issn = {1873-7064},
abstract = {In this review we explore the potential of P2X7 receptor blockers to elicit neuroprotection. This conjecture is based on a reasonably well-established role of this receptor in activating glial cells to maintain a chronic low-level neuroinflammatory state in the brain of patients suffering some neurodegenerative diseases (NDDs). In this context we briefly discuss evidence supporting the role of P2X7 receptors (P2X7) in the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. From a pathogenic point of view these diseases have specific features but all share a low level neuroinflammatory state with microglia activation and enhanced P2X7 expression. Next, we comment on available P2X7 blockers with central nervous system (CNS) target engagement. Then, we deal with the proof-of-concept concerning the potential of some blockers to mitigate the neuroinflammatory state in preclinical models of the target diseases above mentioned. We follow with a discussion of the scarce number of clinical trials done with some P2X7 blockers in inflammatory diseases. Finally, we discuss the current discrepancy between promising preclinical data and the limited number of clinical trials exploring P2X7 antagonists in NDDs. We provide some clues that may boost clinical trials with single P2X7 blockers but particularly, with their association with other medicines currently being used or that are intended to be prescribed in the treatment of NDDs.},
}

@article {pmid41671691,
year = {2026},
author = {da Silva, AMP and de Deus, O and Januário Campos Cardoso, L and Virgilio Ribeiro, F and Froelich Meldola, P and Rodrigues Menezes, I and Lee Han, M and Quiroga, DG and James Almeida, K and Haddad Santos, D and Perry, G and Høilund-Carlsen, PF and de Souza Franco, E and de Sousa Maia, MB},
title = {Efficacy, safety, and ARIA risk of anti-β-amyloid antibodies in early Alzheimer's disease: a systematic review, meta-analysis, and meta-regression.},
journal = {Expert opinion on biological therapy},
volume = {},
number = {},
pages = {},
doi = {10.1080/14712598.2026.2631536},
pmid = {41671691},
issn = {1744-7682},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of dementia and has been closely linked to β-amyloid accumulation. However, the efficacy and safety of anti-β-amyloid monoclonal antibodies remain debated.

METHODS: We systematically searched PubMed, Embase, and Cochrane databases for RCTs comparing anti-β-amyloid monoclonal antibodies with placebo in early-stage AD. Eligible trials enrolled participants with biomarker-supported AD and reported global, cognitive, or safety outcomes, including the CDR-SB, ADAS-Cog 13/14, ARIA, and brain volumetric measures.

RESULTS: Six RCTs including 7837 participants were analyzed. Mean age ranged from 69.8 to 75.4 years, and 57.4% were APOE ε4 carriers. Anti-β-amyloid therapy was associated with small differences in global and cognitive outcomes, best described as a modest slowing of decline on the CDR-SB and ADAS-Cog scales. Treatment was associated with increased risks of ARIA-E (RR, 9.40; 95% CI, 6.98-12.66) and ARIA-H (RR, 2.40; 95% CI, 2.08-2.78), as well as greater ventricular enlargement and hippocampal atrophy.

CONCLUSION: In early AD, anti-β-amyloid monoclonal antibodies are associated with modest slowing of decline accompanied by increased ARIA risk and unfavorable structural brain changes, limiting clinical applicability.

PROTOCOL REGISTRATION: http://www.crd.york.ac.uk/prospero identifier is CRD420251071393.},
}

@article {pmid41671614,
year = {2026},
author = {Li, Z and Tan, B and Dong, K and Yu, X and Zhang, SW and Luo, L and Yao, W and Qin, Z and Wu, F},
title = {Cobrotoxin mitigates neuroinflammation and cognitive impairment by suppressing CD8[+] T cell-microglia interactions in male 5 × FAD mice.},
journal = {Biochemical pharmacology},
volume = {247},
number = {},
pages = {117779},
doi = {10.1016/j.bcp.2026.117779},
pmid = {41671614},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline accompanied by chronic neuroinflammation. Emerging evidence implicates T-cell infiltration and microglial activation as key immune events that accelerate AD pathology, yet therapeutic approaches targeting this neuroimmune interface remain scarce. Cobrotoxin (CTX), a short-chain neurotoxin derived from Naja atra venom, exhibits potent anti-inflammatory and immunomodulatory properties and is clinically approved in China for the treatment of chronic pain syndromes. Here, we investigated whether CTX could alleviate neuroinflammation and cognitive deficits in 5 × FAD mice, a transgenic model of AD. Intranasal CTX administration for nine weeks enhanced spatial learning and memory in the Morris water maze without altering amyloid-β burden. Flow cytometry and immunofluorescence revealed that CTX markedly reduced brain-infiltrating CD8[+] T cells and downregulated chemokines implicated in T cell-microglia communication, including Cxcl9, Cxcl10, Cxcl16, and Ccl5. Consistent with this, CTX attenuated microglial activation and pro-inflammatory cytokine release while preserving plaque-associated microglia (disease-associated microglia, DAM). Morphological and electrophysiological analyses demonstrated that CTX restored dendritic complexity, spine density, and hippocampal long-term potentiation (LTP), indicating improved synaptic integrity. Collectively, these findings identify CTX as a potent modulator of neuroimmune signaling that mitigates neuroinflammation and synaptic dysfunction in AD, suggesting its potential for repurposing as an immunomodulatory therapy for neurodegenerative diseases.},
}

@article {pmid41670689,
year = {2026},
author = {Abedi, A and Foroutan, T and Dargahi, L},
title = {Intranasal CM-hMSCs modulate brain gene expression linked to glucose metabolism and inflammation in male and female rats exposed to maternal and post-weaning high-fat diets.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41670689},
issn = {1432-1912},
support = {4001774//Iran National Science Foundation (INSF)/ ; 26822//Research Affairs of Shahid Beheshti University of Medical Sciences/ ; },
abstract = {Peripheral metabolic disorders, which drive brain insulin resistance, increase the risk of cognitive impairment, a key contributor to Alzheimer's disease. Conditioned media derived from human mesenchymal stem cells (CM-hMSCs) have shown potential for modulating neurological pathways. Male and female offspring exposed to maternal and post-weaning high-fat diet (HFD) were treated with CM-hMSCs. Spatial memory and anxiety-like behaviors were assessed along with hippocampal markers of glucose metabolism, inflammation, and Alzheimer's disease-related pathways. In male offspring, CM-hMSCs partially improved molecular pathways involved in brain glucose metabolism, as indicated by increased hippocampal mRNA expression of Glut1, Glut4, and IDE, and elevated BDNF levels. CM-hMSC treatment also modulated the inflammatory profile, with increased IL-10 and reduced IL-1β in the hippocampus. However, CM-hMSCs did not produce significant improvements in behavioral outcomes. CM-hMSCs exert early, region-specific molecular effects on hippocampal glucose metabolism and inflammatory responses in HFD-exposed male offspring.},
}

@article {pmid41670187,
year = {2026},
author = {Bourgeat, P and Fripp, J and Lebrat, L and Xia, Y and Feizpour, A and Cox, T and Zisis, G and Gillman, A and Goyal, MS and Tosun, D and Benzinger, TL and LaMontagne, P and Breakspear, M and Lupton, MK and Short, C and Adam, R and Robertson, JS and Sperling, R and O'Bryant, SE and Johnson, SC and Jr, CRJ and Schwarz, CG and Barkhof, F and Farrar, G and Bollack, A and Collij, LE and Landau, S and Koeppe, R and , and , and , and , and , and , and , and , and , and , and , and Morris, JC and Weiner, MW and Villemagne, VL and Masters, CL and Rowe, CC and Dore, V},
title = {AI-enhanced Centiloid quantification of amyloid PET images.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71162},
doi = {10.1002/alz.71162},
pmid = {41670187},
issn = {1552-5279},
support = {GA16788//National Health and Medical Research Council/ ; R01-AG058676-01A1/NH/NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; *Deep Learning ; Female ; Aged ; *Brain/diagnostic imaging/metabolism ; *Neuroimaging/methods ; Australia ; },
abstract = {INTRODUCTION: The Centiloid scale is the standard for amyloid (Aβ) PET quantification in research and clinical settings. However, variability between tracers and scanners remains a challenge.

METHODS: This study introduces DeepSUVR, a deep learning method to correct Centiloid quantification, by penalizing implausible longitudinal trajectories during training. The model was trained using data from 2,129 participants (7,149 Aβ positron emission tomography [PET] scans) in the Australian Imaging, Biomarkers and Lifestyle Study of ageing (AIBL)/Alzheimer's Disease Neuroimaging Initiative (ADNI) and validated using 15,807 Aβ PET scans from 10,543 participants across 10 external datasets.

RESULTS: DeepSUVR increased correlation between tracers, and reduced variability in the Aß-negatives. It showed significantly stronger association with cognition, visual reads, neuropathology, and increased longitudinal consistency between studies. DeepSUVR also increased the effect size for detecting small treatment related slowing of amyloid accumulation in the A4 study.

DISCUSSION: DeepSUVR substantially advances Aβ PET quantification, outperforming all standard approaches, which is particularly important for clinical decision making and to detect subtle or early changes in Aβ.

HIGHLIGHTS: Novel artificial intelligence (AI)-method that penalizes biologically implausible longitudinal trajectories, enabling the model to learn standardized uptake value ratios (SUVR) correction factors without requiring longitudinal data at inference time. Improves Centiloid consistency across tracers and studies, significantly enhancing cross-sectional and longitudinal amyloid positron emission tomography (PET) quantification. DeepSUVR-derived Centiloids show stronger associations with cognition, visual reads, and neuropathology. Longitudinal variability is reduced three- to five-fold, enabling more reliable tracking of amyloid accumulation and better detection of treatment effects. Novel reference and target masks derived from DeepSUVR replicate most of the model's performance, offering a practical alternative for integration into existing pipelines.},
}

Humans
*Positron-Emission Tomography/methods
*Alzheimer Disease/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
Male
*Deep Learning
Female
Aged
*Brain/diagnostic imaging/metabolism
*Neuroimaging/methods
Australia

@article {pmid41668753,
year = {2026},
author = {Giff, AE and Wruble Clark, M and Bhattacharyya, S and Sage, PT and Madore, B and Guenette, JP and Miyawaki, EK},
title = {Deep cervical lymph node analysis in central nervous system inflammatory disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1747114},
pmid = {41668753},
issn = {1664-3224},
mesh = {Humans ; *Lymph Nodes/immunology/pathology ; Animals ; *Neuroinflammatory Diseases/immunology ; Glymphatic System/immunology ; },
abstract = {A previously espoused notion that the brain is an immune-privileged organ has been challenged by evidence of bidirectional communication between the central nervous system and the periphery. A well-described "glymphatic" system in the brain and the meningeal lymphatic system serve as conduits through which antigens, immune cells, and metabolic waste travel from the brain to the deep cervical lymph nodes. These nodes, which are more than passive drainage points, serve as locales where dendritic cells, T cells, and B cells interact with central nervous system-derived signals and modulate immune responses that can influence the brain itself. Disruption of clearance mechanisms to deep cervical nodes-due to intracranial vascular disease, aging, poor sleep, chronic inflammation, or other etiologies-may lead to immune dysregulation. Abnormalities in lymphatic drainage can also alter the presentation of antigens from the central nervous system, affect lymphocyte trafficking, and contribute to the aggregation of proteins like β-amyloid, tau, and α-synuclein. This review synthesizes current knowledge on glymphatic and meningeal lymphatic anatomy and function, highlights how impaired drainage contributes to disorders including multiple sclerosis, Alzheimer disease, and Parkinson disease, and discusses the emerging role of deep cervical lymph node imaging and immunophenotyping in assessing neuroinflammation. Finally, we consider how modulation of meningeal lymphatic and nodal function, through pharmacologic or physical interventions, may impair or restore drainage and alter the course of disease in various ways. The integration of advanced imaging with immunological analysis ultimately may enhance the diagnosis, monitoring, and treatment of neuroinflammatory and neurodegenerative diseases. We propose that deep cervical lymph nodes represent an understudied locale, and, potentially, a therapeutic target for peripheral interventions to influence brain disease trajectories.},
}

Humans
*Lymph Nodes/immunology/pathology
Animals
*Neuroinflammatory Diseases/immunology
Glymphatic System/immunology

@article {pmid41668551,
year = {2026},
author = {Gao, C and Li, Y and Zhou, B and Liu, Y and Hao, MQ and Sun, H and Jin, Z and Li, LL and Yang, XF and Guo, XL and Yin, Y},
title = {The application of exosomes derived by mesenchymal stem cell from different tissues in the management of Alzheimer's disease.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17435889.2026.2629030},
pmid = {41668551},
issn = {1748-6963},
abstract = {With the intensifying global trend of population aging, the treatment of Alzheimer's disease (AD) faces significant challenges. Current therapeutic approaches can only temporarily alleviate symptoms without halting or reversing disease progression. Numerous studies on mesenchymal stem cell-derived exosomes (MSC-Exos) suggest that, compared to stem cell therapy, MSC-Exos offer considerable advantages in the treatment of AD. This review examines the various mechanisms by which exosomes produced from MSCs function as therapeutic agents for AD. Additionally, it provides a concise overview of the research conducted on MSC-Exos for AD, categorized by tissue source. The text also provides an account of the ongoing clinical trials involving MSC-Exos and examines their benefits, drawbacks, and potential avenues for future research.},
}

@article {pmid41668547,
year = {2026},
author = {Zhang, Y and Wang, J and Yuan, J and Li, S and Sun, Y},
title = {FA-2-b-β modulates HMGB1/NF-κB/NLRP3 signaling to alleviate neuroinflammation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418300},
doi = {10.1177/13872877261418300},
pmid = {41668547},
issn = {1875-8908},
abstract = {BackgroundFA-2-b-β, an extract derived from traditional Chinese medicine (TCM), has been suggested as a potential neuroprotective agent.ObjectiveThis study aimed to elucidate its role in modulating HMGB1-mediated inflammation and pyroptosis in Alzheimer's disease (AD), with a particular emphasis on the interaction between FA-2-b-β and HMGB1.MethodsAD cell and animal models were used to examine the effect of FA-2-b-β on HMGB1/NF-κB/NLRP3 signaling pathway. Protein expression levels were detected by western blotting, and enzyme-linked immunosorbent assay (ELISA), respectively. Immunofluorescence staining was performed to determine the cellular localization of key proteins. The role of HMGB1 in amyloid-β (Aβ)-induced neuroinflammation and pyroptosis was examined through siRNA-mediated HMGB1 knockdown. Behavioral tests were conducted in AD animal models to evaluate cognitive improvements following FA-2-b-β treatment.ResultsIn cellular models, FA-2-b-β significantly suppressed Aβ-induced overexpression HMGB1 and inhibited the activation of NF-κB, which consequently led to a reduction in the formation of the NLRP3 inflammasome. This suppression resulted in decreased of activation caspase-1 and lower levels of IL-1β and IL-18, thereby alleviating pyroptosis and neuroinflammation. The knockdown of HMGB1 further corroborated its role in mediating Aβ-induced inflammatory responses. In AD animal models, treatment with FA-2-b-β attenuated neuroinflammation, preserved neuronal integrity, and enhanced cognitive function.ConclusionsFA-2-b-β exhibits a capacity to modulate the HMGB1/NF-κB/NLRP3 signaling pathway, thereby mitigating neuroinflammation and pyroptosis, highlighting its potential as a therapeutic intervention for AD.},
}

@article {pmid41668529,
year = {2026},
author = {Wang, W and Chen, Y and Xiong, Z and Wang, Z and Ye, W and Li, X},
title = {Donepezil Research in Cognitive Impairment: A Bibliometric and Scientometric Analysis of Global Trends and Pharmacological Perspectives.},
journal = {Brain and behavior},
volume = {16},
number = {2},
pages = {e71251},
doi = {10.1002/brb3.71251},
pmid = {41668529},
issn = {2162-3279},
support = {//Neurosurgery First-class Discipline Funding Project of the Second Affiliated Hospital of Harbin Medical University/ ; },
mesh = {*Donepezil/therapeutic use/pharmacology ; Humans ; *Bibliometrics ; *Cognitive Dysfunction/drug therapy ; Alzheimer Disease/drug therapy ; Cholinesterase Inhibitors/therapeutic use/pharmacology ; *Nootropic Agents/therapeutic use/pharmacology ; Biomedical Research ; },
abstract = {BACKGROUND: Cognitive impairment (CI) greatly affects global health and quality of life. Donepezil, a widely used treatment for CI, particularly in Alzheimer's disease, has been extensively studied; however, a comprehensive bibliometric analysis summarizing global research trends remains limited.

METHODS: Relevant English-language articles and reviews published between 2000 and 2025 were retrieved from the Web of Science Core Collection. CiteSpace and VOSviewer were employed to analyze publication trends, collaborative networks, journal distribution, co-citation patterns, and keyword co-occurrence.

RESULTS: A total of 1907 publications were identified. The United States led in both output and citation impact, with the University of Toronto emerging as the most influential institution. The U.S. Department of Health and Human Services provided the greatest funding support. The Journal of Alzheimer's Disease was the primary publishing outlet, and Etsuro Mori was the most prolific and influential author. Keyword analysis revealed "Donepezil," "Alzheimer's disease," and "Mild cognitive impairment" as dominant terms. Recent hotspots-such as "acetylcholinesterase," "oxidative stress," "neuroinflammation," "tau protein," and "mechanism"-reflect a shift toward mechanistic and preclinical research.

CONCLUSION: Research on donepezil for CI has shown consistent growth, evolving from clinical application toward mechanistic exploration and disease modification. Future studies are expected to focus on individualized therapy, combination strategies, and underexplored CI subtypes, aiming to enhance the therapeutic potential and clinical value of donepezil.},
}

*Donepezil/therapeutic use/pharmacology
Humans
*Bibliometrics
*Cognitive Dysfunction/drug therapy
Alzheimer Disease/drug therapy
Cholinesterase Inhibitors/therapeutic use/pharmacology
*Nootropic Agents/therapeutic use/pharmacology
Biomedical Research

@article {pmid41668484,
year = {2026},
author = {Wang, Q},
title = {[Current status and future perspectives on age-related hearing loss and cognitive impairment].},
journal = {Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery},
volume = {40},
number = {3},
pages = {220-225},
doi = {10.13201/j.issn.2096-7993.2026.03.002},
pmid = {41668484},
issn = {2096-7993},
mesh = {Humans ; Aged ; *Presbycusis ; *Cognitive Dysfunction ; *Cognition Disorders ; *Hearing Loss ; Aging ; },
abstract = {Objective:Age-related hearing loss（ARHL） is one of the most common sensory degenerative disorders in the elderly, characterized by high prevalence, insidious onset, and progressive deterioration. Recent studies indicate that ARHL not only impairs communication and quality of life in older adults, but is also significantly associated with the development of cognitive impairment and Alzheimer's disease. However, its underlying pathogenesis remains incompletely understood, and the relationship between clinical phenotypes of ARHL and cognitive decline has yet to be clearly defined. ARHL occupies a pivotal position in geriatric health management and in the prevention of neurodegenerative diseases, yet it has not been systematically conceptualized or mechanistically examined. In this review, we summarize the current research progress on ARHL and cognitive impairment, analyze possible mechanisms linking the two conditions, evaluate the potential cognitive protective effects of hearing interventions, and propose priority directions for future research and clinical practice. With advances in multidisciplinary collaboration and technological innovation, the prevention and treatment of ARHL are expected to enter a new era of greater precision and efficiency, offering novel opportunities to reduce the risk of cognitive impairment and improve overall health in older populations.},
}

Humans
Aged
*Presbycusis
*Cognitive Dysfunction
*Cognition Disorders
*Hearing Loss
Aging

@article {pmid41669706,
year = {2024},
author = {Hoang, B and Pang, Y and Dodge, H and Zhou, J},
title = {Translingual Language Markers for Cognitive Assessment from Spontaneous Speech.},
journal = {Interspeech},
volume = {2024},
number = {},
pages = {977-981},
pmid = {41669706},
issn = {2958-1796},
abstract = {Mild Cognitive Impairment (MCI) is considered a prodromal stage of dementia, including Alzheimer's disease. It is characterized by behavioral changes and decreased cognitive function, while individuals can still maintain their independence. Early detection of MCI is critical, as it allows for timely intervention, enrichment of clinical trial cohorts, and the development of therapeutic approaches. Recently, language markers have been shown to be a promising approach to identifying MCI in a non-intrusive, affordable, and accessible fashion. In the InterSpeech 2024 TAUKADIAL Challenge, we study language markers from spontaneous speech in English and Chinese and use the bilingual language markers to identify MCI cases and predict the Mini-Mental Status Examination (MMSE) scores. Our proposed framework combines the power from 1) feature extraction of a comprehensive set of bilingual acoustic features, and semantic and syntactic features from language models; 2) careful treatment of model complexity for small sample size; 3) consideration of imbalanced demographic structure, potential outlier removal, and a multi-task treatment that uses the prediction of clinical classification as prior for MMSE prediction. The proposed approach delivers an average of 78.2% Balanced Accuracy in MCI detection and an averaged RMSE of 2.705 in predicting MMSE. Our empirical evaluation shows that translingual language markers can improve the detection of MCI from spontaneous speech. Our codes are provided in https://github.com/illidanlab/translingual-language-markers.},
}

@article {pmid41667430,
year = {2026},
author = {Rossini, PM and Pappalettera, C},
title = {Should all MCI with Alzheimer's biological diagnosis receive anti-amyloid therapy?.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08456-z},
pmid = {41667430},
issn = {2041-4889},
abstract = {Our perspective addresses one of the most pressing and timely debates in contemporary neurology and health policy: whether the recent approval of anti-amyloid monoclonal antibodies for Alzheimer's disease should extend to all individuals with mild cognitive impairment (MCI; a large population of tens of millions of individuals worldwide mainly represented in Countries with aged population) who test positive for amyloid biomarkers, despite wide variability in prognosis and therapeutic response and the epidemiological demonstration that only about half of them manifest symptoms of dementia. The manuscript highlights three central themes. First, while epidemiological and meta-analytic data confirm that MCI significantly increases the risk of dementia, more than half of affected individuals-many of whom are biomarker-positive for amyloid/tau-do not progress to dementia even over long- term follow-up. Second, recently approved anti-amyloid therapies, although representing a landmark in disease-modifying treatments, carry high costs, non-negligible risks (particularly amyloid-related imaging abnormalities), and uncertain long-term real-world benefits. Third, indiscriminate prescription of these agents risks exposing large numbers of subjects to unnecessary harm while placing unsustainable burdens on healthcare systems. We argue that the field should urgently move to identify and validate accurate and sustainable instruments for risk-stratified treatment pathways, integrating genetic, clinical, neuropsychological, neuroimaging, and fluid biomarker data including risk and resilience factors to refine prognostication. In addition, we call on the scientific community, journals, and policymakers to foster dialog that bridges neurology, geriatrics, bioethics, health economics, and patient advocacy, so that clinical innovation is matched by ethical responsibility and equitable implementation.},
}

@article {pmid41667287,
year = {2026},
author = {Casper, A and Bolin, J},
title = {Alzheimer Disease and the Utility of PET.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271758},
pmid = {41667287},
issn = {1535-5675},
abstract = {Alzheimer disease (AD) is the most common cause of dementia and one of the leading causes of death in adults age 65 y or older in the United States. AD presents with symptoms of cognitive impairment that worsen with disease progression, ultimately affecting an individual's functional abilities, independence, and overall health. Historically, treatment has relied on the mitigation of the adverse effects of the disease; however, the recent development of antiamyloid monoclonal antibodies allows for the targeting of pathologic factors that drive the progression of disease. Nuclear medicine has established itself as a useful tool in the evaluation of AD through the use of PET tracers, which target pathologic biomarkers such as amyloid-β and tau proteins, as well as metabolic processes reflective of neurodegenerative damage. Amyloid-β PET imaging and quantification have recently gained interest for their ability to more effectively diagnose AD and identify patients eligible for treatment with new antiamyloid therapies.},
}

@article {pmid41667282,
year = {2026},
author = {Grabher, BJ},
title = {Centiloids in Amyloid PET: A Practical Guide to Quantitation Interpretation.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271823},
pmid = {41667282},
issn = {1535-5675},
abstract = {The approval of disease-modifying antiamyloid therapies has expanded the clinical role of amyloid PET beyond diagnostic confirmation to include baseline characterization and longitudinal monitoring of treatment response. Although visual interpretation remains the clinical standard for amyloid PET, it may be limited in borderline cases and when assessing subtle changes in amyloid burden over time. Quantitative amyloid PET provides objective measures that complement visual assessment, with z scores, SUV ratios, and Centiloid scaling offering increasing clinical utility. The Centiloid scale standardizes amyloid PET quantification across tracers, scanners, and institutions by anchoring measurements to biologically defined reference points, enabling consistent interpretation and comparison. This article describes the principles of amyloid PET quantification, explains the origin and interpretation of Centiloids, and discusses their role in therapy monitoring and clinical decision-making. Understanding quantitative amyloid PET and its limitations is essential for nuclear medicine professionals in the evolving landscape of Alzheimer disease imaging.},
}

@article {pmid41667280,
year = {2026},
author = {Skyles, T and Bouchal, SM and Giarratana, A and Wengler, J and Hart, I and Greig, E and Singh, H and Huang, SS and Martinez, F and Nguyen, B and Shin, CH and Yang, M and Parent, E and Robb, WH and Franceschi, AM and Burkett, B and Johnson, D and Koran, ME},
title = {PET Imaging in Alzheimer Disease in the Era of Antiamyloid Therapy in the United States: Clinical Utility, Quantification, and Policy Landscape.},
journal = {Journal of nuclear medicine technology},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnmt.125.271835},
pmid = {41667280},
issn = {1535-5675},
abstract = {Alzheimer disease (AD) is increasingly diagnosed using molecular imaging biomarkers. PET imaging provides the opportunity to visualize amyloid and tau aggregates and in vivo neurodegenerative changes. These techniques provide exciting new avenues toward diagnosis, disease staging, and therapeutic monitoring of AD. Methods: This review details recent advances in amyloid PET, tau PET, and [18]F-FDG PET as they relate to the diagnosis, staging, and treatment of AD. The increasing roles of PET in the biologically based diagnosis of AD and antiamyloid immunotherapy response monitoring are addressed. Results: Amyloid PET enables improved detection of amyloid-β plaques within the brain. Amyloid PET is increasingly vital for confirming AD diagnoses given the emergence of antiamyloid immunotherapies, which require biomarker-verified amyloid positivity to initiate treatment. Tau PET provides a direct measure of neurofibrillary tangle pathology and is useful for disease staging, the interpretation of atypical clinical presentations, and treatment decision-making. [18]F-FDG PET plays a vital role in distinguishing AD from other dementia subtypes. Expanded reimbursement policies for amyloid and tau PET have increased accessibility to these modalities. Finally, quantitative methods facilitate interscan reproducibility and permit therapeutic monitoring. Conclusion: Molecular neuroimaging is poised to play a central role in the biologic definition, diagnosis, staging, and management of AD. Integrating amyloid, tau, and FDG PET with clinical assessments and fluid biomarkers provides earlier and more accurate diagnoses, opening the door to personalized treatment.},
}

@article {pmid41666775,
year = {2026},
author = {Chaudhari, S and Shinde, A and Salunke, M and Bairagi, S and Dhage, A and Patel, P and Rathod, V and Pathare, S and Altwaijry, N and Khan, MS},
title = {Investigating the anti-Alzheimer potential of biogenic compounds from Zinc15 database as NMDA antagonist: An in-silico approach.},
journal = {Journal of molecular graphics & modelling},
volume = {144},
number = {},
pages = {109277},
doi = {10.1016/j.jmgm.2026.109277},
pmid = {41666775},
issn = {1873-4243},
abstract = {Alzheimer's disease is an unavoidable neurological disorder in which the death of brain cells brings on memory loss, cognitive decline, and eventual dementia. There is no recognized treatment for Alzheimer's illness. By the year 2050, it is expected that the global population will witness approximately 100 million cases of Alzheimer's disease (AD). Despite recognizing AD as a formidable illness for over a century, no effective cure has been discovered thus far. Synaptic dysfunction could result from disturbed synaptic calcium handling caused by excessive activation of glutamate receptors, particularly the N-methyl-D-aspartate receptors (NMDARs). Glutamate serves as the brain's primary excitatory neurotransmitter, acting on ionotropic and metabotropic glutamate receptors. In recent years, several pharmacologically active substances derived from plants, animals, and microbes have shown promise in treating AD by focusing on various pathogenic processes. Initially, we used virtual screening to assess natural product-like compounds against NMDA receptors. In this research study, we have screened a natural compound database derived from zinc15. The best candidate was then validated through molecular dynamics simulation (MDS). The results revealed that out of 4221 compounds tested, only 165 showed superior binding interactions compared to native ligands, making them inhibitors for protein. Further analysis using ADMET indicates favorable drug-like properties, particularly for CNS drug-likeness. The MDS results, including RMSD, RMSF, Rg, and residue interactions, indicated a strong and stable association between top molecules and target protein. This confirms that top molecules can effectively remain within the binding pockets of the target proteins, forming stable protein-ligand complexes.},
}

@article {pmid41666521,
year = {2026},
author = {Qin, Z and Wang, Z and Gao, C and Yong, X and Hua, Y and Zhou, Y and Xie, J},
title = {Ultrasound-mediated blood-brain barrier opening for targeted neurological drug delivery.},
journal = {Biomaterials advances},
volume = {183},
number = {},
pages = {214754},
doi = {10.1016/j.bioadv.2026.214754},
pmid = {41666521},
issn = {2772-9508},
abstract = {Neurological disorders represent a devastating global health crisis, and the blood-brain barrier (BBB) remains a major obstacle for their treatment. Conventional strategies for BBB opening, including direct intracranial injection, osmotic disruption, receptor-mediated transcytosis, and nanoparticle carriers, often suffers from surgical invasiveness, systemic toxicity, poor biodistribution, and off-target effects. Ultrasound-mediated drug delivery has emerged as a revolutionary non-invasive technology for transient and targeted BBB opening, enabling enhanced penetration of therapeutic agents into the central nervous system. This review comprehensively summarizes the mechanisms underlying ultrasound-based delivery with focus on current delivery platforms including microbubble (MB)-assisted, nanoparticle-based, and MB-nanoparticle composite strategies. Furthermore, we highlight recent advances in the application of focused ultrasound (FUS) combined with MBs for the treatment of Alzheimer's disease, Parkinson's disease, and glioma. Finally, we discuss emerging technologies such as sonodynamic therapy and ultrasound-controlled magnetic nanorobots, while also addressing current challenges in this field. This review underscores the transformative potential of ultrasound-mediated drug delivery as a versatile platform for precision neurology. It also prospects future directions for advancing multidisciplinary research and clinical translation.},
}

@article {pmid41666126,
year = {2026},
author = {Yue, J and Jones, B and Tran, KH and Deen, M and Holicek, V and Cheng, WH and Michalik, M and Power, S and Wellington, CL and Watson, NV and Vocadlo, DJ},
title = {Pharmacological inhibition of O-GlcNAcase reduces pS129-α-synuclein positive aggregates in the substantia nigra of mThy1-hSNCA mice.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X251410291},
doi = {10.1177/1877718X251410291},
pmid = {41666126},
issn = {1877-718X},
abstract = {BackgroundThe aggregation and spread of α-synuclein within brain are associated with the loss of dopaminergic neurons and the formation of Lewy bodies as seen in Parkinson's disease. Blocking the initiation of α-synuclein aggregation, or the spread of such aggregates, may offer disease-modifying approaches to slow disease progression. Previous studies have demonstrated that modification of aggregation prone proteins, including α-synuclein, with O-linked β-N-acetylglucosamine (O-GlcNAc) reduces their aggregation. Small molecule inhibitors of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, confers neuroprotective benefits in various preclinical disease models of Alzheimer's and Parkinson's diseases.ObjectiveThis study investigates the effects of long-term pharmacological enhancement of O-GlcNAcylation in a transgenic mouse model of Parkinson's disease overexpressing human α-synuclein.MethodsThiamet-G was orally administered to mThy1-hSNCA and wild-type (WT) mice for ten months. Behavioral assessments were conducted to examine changes in locomotion and cognition. Histological analyses were performed to analyze α-synuclein aggregates and dopaminergic neurons in brain sections. Immunoblot and ELISA analyses were performed to analyze O-GlcNAc and soluble α-synuclein using brain lysates, respectively.ResultsThiamet-G increased the level of O-GlcNAc in the brain of both mThy1-hSNCA and WT mice. The levels of total α-synuclein in the brain were unaltered. However, Thiamet-G strongly attenuated the deposition of pS129-immunoreactive α-synuclein aggregates within the substantia nigra, prior to observable neurodegeneration. Thiamet-G also protected against locomotor decline.ConclusionsThese results support OGA inhibition as a therapeutic approach to block the pathological formation of toxic α-synuclein as a disease-modifying treatment against Parkinson's disease.},
}

@article {pmid41666058,
year = {2026},
author = {Zhang, H and Wang, D and Yang, J and Zhao, Y and Liu, Y and Zhu, R and Wang, L and Song, R and Zhang, W},
title = {Unsupervised Disentanglement of Brain Heterogeneity for Identifying Subtypes of Alzheimer's Disease.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2026.3663181},
pmid = {41666058},
issn = {1558-2531},
abstract = {Neuroanatomical heterogeneity in Alzheimer's disease (AD) hinders precision diagnosis and treatment, as distinct brain phenotypes may correspond to different disease subtypes. However, MRI-based subtype classifications are often confounded by co-occurring pathologies and non-AD factors, such as genetic predisposition and environmental influences, limiting their clinical interpretability. We propose 3D-DisAD, an unsupervised deep learning framework that disentangles AD-specific neuroanatomical variations from unrelated influences and clusters patients into subtypes with homogeneous brain phenotypes. The framework comprises two synergistic networks: (1) Contrastive Disentanglement Network, which separates AD-specific variations from those shared by AD patients and healthy controls; and (2) Transformation Generation Network, which refines these disease-specific variations by transforming healthy brain representations into realistic, pathology-consistent anatomies via diffusion-based generative modeling. Evaluated on four public datasets, 3D-DisAD reveals strong correlations between the disentangled AD-specific variations and diverse clinical and biological profiles, validating their relevance. Using these variations, we identify four AD subtypes with significant differences in biomarkers, cognitive trajectories, and genetic signatures, and uncover distinct longitudinal progression patterns that suggest potential windows for early intervention. By disentangling AD-specific variations, our method enables more precise patient stratification and personalized treatments, particularly in the early stage of AD. Code is available at: https://github.com/cnuzh/3D-DisAD.},
}

@article {pmid41665751,
year = {2026},
author = {Voronova, AD and Karsuntseva, EK and Shishkina, VS and Chadin, AV and Fursa, GA and Gurin, PI and Kuznetsova, TV and Reshetov, IV and Shport, SV and Stepanova, OV and Chekhonin, VP},
title = {Clinical Trials of Cell Products for the Treatment of Alzheimer's Disease (Review).},
journal = {Bulletin of experimental biology and medicine},
volume = {},
number = {},
pages = {},
pmid = {41665751},
issn = {1573-8221},
abstract = {Existing approaches to the treatment of Alzheimer's disease are ineffective because they do not stop neurodegenerative processes in the brain and do not promote the regeneration of the nervous tissue. Cell therapy is a promising strategy for the treatment of this disease. This review discusses clinical studies of cell-based therapies for Alzheimer's disease, evaluates their therapeutic potential, and proposes strategies for developing safe, accessible, and effective cell products.},
}

@article {pmid41665706,
year = {2026},
author = {Giacomini, PS and Voss, P and Devonshire, V and Schneider, R and Macaron, G and Hussein, S and Blanchette, F and de Villers-Sidani, É},
title = {Eye tracking as a digital biomarker in neurodegenerative diseases.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {133},
pmid = {41665706},
issn = {1432-1459},
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology/complications ; Biomarkers ; *Eye-Tracking Technology ; *Eye Movements/physiology ; },
abstract = {Oculomotor abnormalities are a common finding in neurodegenerative diseases due to degeneration of neural pathways and brain regions involved in controlling eye movements. Pathological changes to the dorsolateral prefrontal cortex, basal ganglia, superior colliculus and cerebellum produce subtle changes in eye-movement metrics that may not be detected by clinical examination. The present review addresses the potential use of eye-movement biomarkers in neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Alzheimer's disease and other dementias, and amyotrophic lateral sclerosis. Eye-movement metrics such as saccades, anti-saccades, fixation and smooth pursuit are prognostic of disease progression, can differentiate pathologic subtypes as an aid to diagnosis, and enable clinicians to evaluate early worsening of motor and cognitive function. The cost of medical technologies limits their optimal use and accessibility in clinical practice. The shortage of subspecialist neurologists further limits access to care. New eye-tracking technologies incorporated into widely-accessible digital devices such as smart phones and tablets now permit detailed assessments with minimal equipment requirements, providing an important non-invasive and potentially cost-effective method for patient evaluation in routine clinical practice and as an aid to treatment decision-making. Digital biomarkers can be readily employed by healthcare professionals such as family physicians, nurses and pharmacists to bridge the care gaps, potentially providing them with powerful tools that can be broadly adopted to improve the delivery of care to patients with neurodegenerative conditions.},
}

Humans
*Neurodegenerative Diseases/diagnosis/physiopathology/complications
Biomarkers
*Eye-Tracking Technology
*Eye Movements/physiology

@article {pmid41664707,
year = {2026},
author = {Xiang, Q and Shi, RL and Huang, YX and Liu, LN and Tao, JS and Li, XH and Li, XD},
title = {Oligodendrocyte: Development, Plasticity, Biological Functions, Diseases, and Therapeutic Targets.},
journal = {MedComm},
volume = {7},
number = {2},
pages = {e70618},
pmid = {41664707},
issn = {2688-2663},
abstract = {In the past few years, the incidence rate of central nervous system (CNS) diseases is still growing. Meanwhile, the molecular mechanism on the pathogenesis of neurological diseases remains elusive. Oligodendrocyte progenitor cells (OPCs) are distributed in the whole CNS and represent a population of migrating and proliferating adult progenitor oligodendrocytes that can be differentiated into oligodendrocytes (OLs). The main function of OLs is to produce myelin, the membrane wrapping tightly around the axon, which are associated with the myelination and remyelination. During regeneration, the new OLs from OPCs can regenerate lost myelin, which prevents axonal degeneration and restores its plasticity and function. Considering these energy-consuming processes, the high metabolic turnover OLs are susceptible to neurotoxic factors and its excitatory toxicity. Thus, the pathogenesis of OPC and OL are proven in neurological diseases, such as multiple sclerosis, Alzheimer's disease, major psychiatric diseases, and epilepsy. The current study reviewed the development, plasticity as well as application of OPCs and OLs researches on CNS diseases. Additionally, the effective methods and bioengineering technologies as well as biomaterials relevant to regenerative medicine are also discussed, which could provide the novel insight into the therapeutic treatment of those diseases, exploring new pathological clues, identifying the key molecules and targets as well as the potential biomarkers.},
}

@article {pmid41664517,
year = {2026},
author = {Silva Fernandes, A and Barbosa de Souza, Á and Benvindo de Souza, M and Madureira Almeida, L and Luiz Franco, O and Luiz Cardoso Bailão, EF and Borges, LL and Sérgio Nakao de Aguiar, A},
title = {DNA damage induced by fungicides triadimefon, triadimenol, and their mixture in human lymphocytes: cytogenotoxicity and computational analysis of metabolic pathways.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/01480545.2026.2626753},
pmid = {41664517},
issn = {1525-6014},
abstract = {Triadimefon (TF) and triadimenol (TN) are triazole fungicides widely used to prevent fungal infections in cereals, fruits, and other economically important crops. Their harmful effects on non-target organisms have been reported. This study investigated the cytogenotoxic effects of TF and TN, isolated and combined, at environmentally relevant concentrations (TF: 0.006, 0.012, and 0.024 mg/mL; TN: 1.5, 3.0, and 6.0 mg/mL; and 0.012 mg/mL TF + 3.0 mg/mL TN) on human lymphocytes using the trypan blue exclusion test and the comet assay. Additionally, in silico tools, BioTransformer and DIGEP-Pred, were employed to elucidate metabolic pathways more effectively for detoxifying these xenobiotics and to evaluate their putative effects on gene transcription, respectively. Exposure to TF and TN, either alone or in combination, did not affect lymphocyte viability at the tested concentrations. However, both compounds induced an increase in the percentage of DNA strand breaks after treatment. The in silico predictions suggested that the interaction with the cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C9, and CYP2D6) differed for each compound analyzed. Gene expression prediction indicated that TF and TN may up-regulate genes involved with hormonal alterations, Alzheimer's disease risk, and cancer progression (SF1, SPON1, ADGRF5, and RORB). While they may down-regulate a gene involved with changes in heart rhythm and neurotoxicity (HCN1). In conclusion, our findings reinforced that the triazole fungicides TF and TN, while effective in agriculture, may pose risks to genomic stability in humans, highlighting the importance of biomonitoring studies in exposed populations.},
}

@article {pmid41664331,
year = {2026},
author = {Siddiqui, S and Tufail, P and Khan, F and Khalid, MF and Khalid, F},
title = {Protocatechuic Acid Alleviates Neurodemyelination by Modulating PKCα-p38/MAPK Pathways in an LPC-Induced Model of Neurodegeneration.},
journal = {Current protein & peptide science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892037385148251207081917},
pmid = {41664331},
issn = {1875-5550},
abstract = {INTRODUCTION: Neuroinflammation, axonal damage, and alterations in extracellular matrix (ECM) protein expression are hallmarks of neurodegenerative diseases. Therapies that enhance recovery from brain injury are of significant clinical value. Therefore, this study investigated the antiinflammatory properties of protocatechuic acid (PCA).

METHODS: Neuroglial cocultures were prepared from P0-P1 rats. Demyelination was induced using LPC (0.003%). The effects of PCA (10 and 25 μg) on neurite outgrowth were assessed using morphometry software. Expression of COX-2, NF-κβ, PKC-α, and p38/MAPK was examined through immunostaining, SDS-PAGE, and Western blotting. Expression intensities were quantified using ImageJ software. Sustained repetitive neuronal firing was evaluated using the patch-clamp technique.

RESULTS: PCA increased neurite outgrowth in LPC-treated cultures after 72 hours in vitro. LPCinduced upregulation of ECM proteins TN-C, LN, and CSPGs was significantly reduced by PCA treatment compared with LPC controls. Similarly, PCA decreased the expression intensities of the pro-inflammatory markers NF-κβ and COX-2 relative to LPC controls. Furthermore, PCA reversed the sustained neuronal firing pattern observed in untreated LPC-exposed neurons.

DISCUSSION: Purified bioactive compounds commonly present in everyday foods show therapeutic potential for Parkinson's and Alzheimer's diseases due to their lower toxicity compared with conventional drugs. Artificial intelligence tools, such as AlphaFold and RoseTTAFold, further support drug development by predicting PCA binding modes with PKCα and P38/MAPK, thereby contributing to the design of personalized therapeutics and advancing neuroscience research.

CONCLUSION: PCA alleviated neuroinflammation by reducing phosphorylation of PKCα and p38/MAPK.},
}

@article {pmid41618017,
year = {2026},
author = {Beccherle, M and Amato, S and Facci, E and Stefanescu, G and Bertagnoli, S and Francesco, VD and Fontana, G and Gambina, G and Moro, V},
title = {Patterns of cognitive and motor decline in Alzheimer's Disease (AD) and ageing in healthy populations.},
journal = {Aging clinical and experimental research},
volume = {38},
number = {1},
pages = {74},
pmid = {41618017},
issn = {1720-8319},
abstract = {BACKGROUND: Various patterns may apply to an individual’s health-span, with quality of life deriving from a balance between physical conditions, motor and cognitive abilities (i.e. psychomotor capabilities).

METHODS: In this study, the Italian version of the Éxamen Geronto-Psychomoteur was administered to a sample of Alzheimer’s Disease (AD) patients (n = 94) and a group of healthy older adults (n = 333) to compare the patterns of psychomotor decline in pathological and physiological ageing. Three domains were considered to integrate bodily and cognitive dimensions: cognitive functions, motor abilities, and muscular tone alterations (physical constraints). Potential correlations with general cognitive functioning, autonomy in daily life, mood and nutritional status were also investigated.

RESULTS: A correlation between cognitive, motor and physical dimensions is confirmed, and the results show that the patterns relating to healthy and pathological ageing are not only quantitatively but also qualitatively different. Besides the cognitive functions, the deterioration in AD also affects the physical components, precociously. Specifically, hypertonia may be present since the initial phases of illness. In healthy subjects, body representations decline early, while verbal memory, temporal and space representation resist over time. Malnutrition correlates with hypertonia in AD and with a reduction in daily life abilities in healthy people.

CONCLUSIONS: The results highlight the importance of adopting an integrated psychomotor approach in the screening, diagnosis and treatment of ageing and AD to investigate early motor and bodily indicators, which are often not fully considered in clinical practice.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40520-026-03327-1.},
}

@article {pmid41527082,
year = {2026},
author = {Du, Y and Wu, L and Mao, Y and Chen, S and Gao, X},
title = {IL-27, a metabolic regulator secreted by astrocytes in response to GLP-1RA OHP2, modulates microglial reprogramming in Alzheimer's disease by regulating cGAS lactylation.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {58},
pmid = {41527082},
issn = {1742-2094},
support = {82473834//National Natural Science Foundation of China,China/ ; 82373780//National Natural Science Foundation of China,China/ ; CPU2022PZQ10//"Double First-Class" University Project/ ; },
abstract = {UNLABELLED: Microglia-mediated neuroinflammation, considered one of the most plausible pathogenic hypotheses underlying Alzheimer’s disease (AD), plays a pivotal role in the initiation and progression of this devastating condition. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated promising neuroprotective effects in both preclinical and clinical studies. Previously, we developed an orally-administered GLP-1RA peptide called OHP2, which is capable of crossing the blood-brain barrier for the treatment of AD. OHP2 has been shown to effectively reduce brain inflammation in AD mouse models. In this study, we discovered that OHP2 treatment induced IL-27 secretion from astrocytes and modulated microglial reprogramming from the neurotoxic M1 phenotype to the neuroprotective M2 phenotype through glycolysis/cGAS lactylation clock/mTOR pathway, thereby alleviating excessive neuroinflammation. These findings provide a rationale for further pharmacological investigations into OHP2 and suggest that IL-27 may hold significant implications for AD therapy as a metabolic regulator.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03683-1.},
}

@article {pmid41663779,
year = {2026},
author = {Roy, KK and Kumari, R and Upadhyay, AK and Mohanty, S},
title = {Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41663779},
issn = {2240-2993},
abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are growing more common worldwide, yet treatment is still poor. Conventional therapies can have unforeseen side effects, produce poor medication reactions, and take longer to work. This persistent treatment gap highlights the need for novel approaches to these disorders' complex distinctions. Pharmacogenomics, which examines how genetic differences affect drug response, is a promising new subject and an urgent solution. Pharmacogenomics tailors medicine selection and administration to each patient's genetic profile, addressing the main causes of poor treatment response and preventable side effects. This research has enabled precision medicine that can improve neurodegenerative disease therapy and reduce harm. In this in-depth research, we examine neurodegenerative disease management issues, pharmacogenomics breakthroughs, and how incorporating genetics to clinical practice can improve outcomes. We examine the latest evidence that genetics affect drug breakdown, efficacy, and toxicity. We also discuss the challenges and opportunities of applying this knowledge. Pharmacogenomic approaches must be widely applied to make medicines for these awful disorders safer, more effective, and really suited to patient needs, according to our compilation.},
}

@article {pmid41662806,
year = {2026},
author = {Zhang, H and Zhang, H and Zhao, M and Luo, W and Chen, S and Wang, P and Liu, X and Xu, S},
title = {Da-Bu-Yin-Wan rescues cognitive deficits in aging and Alzheimer's disease models by Wnt/β-catenin-dependent restoration of lysosomal acidification.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {153},
number = {},
pages = {157916},
doi = {10.1016/j.phymed.2026.157916},
pmid = {41662806},
issn = {1618-095X},
abstract = {BACKGROUND: Lysosomal acidification deficits are increasingly recognized as a convergent pathological mechanism driving both age-related cognitive decline (ARCD) and early Alzheimer's disease (AD) progression, creating a self-reinforcing cycle of cellular aging and Aβ dyshomeostasis. Despite demonstrated neuroprotective effects of Da-Bu-Yin-Wan (DBYW) in Parkinson's disease models, its therapeutic potential for lysosomal dysfunction in ARCD and AD remains an uncharted area of investigation.

PURPOSE: This present work aimed to elucidate the mechanistic basis by which DBYW mitigates both ARCD and AD pathology through functionally rescuing impaired lysosomal acidification.

METHODS: Cell-based D-galactose and Aβ-induced in BV2 cells to study lysosomal acidification. Molecular analyses combined immunofluorescence localization studies with quantitative immunoblotting of lysosomal and Wnt signaling proteins. In vivo, DBYW treatment effects were systematically evaluated in both D-gal-induced and APP/PS1 transgenic models using cognitive behavioral followed by immunohistochemical and biochemical assessment of brain tissues lysosomal parameters and Wnt signaling activity.

RESULTS: DBYW attenuated the mechanistic basis of ARCD and AD pathology by functionally rescuing impaired lysosomal acidification. Overexpression of β-catenin could modulate D-galactose or Aβ-induced dysregulation of the Wnt/β-catenin pathway and restore lysosomes with abnormal acidification, while DBYW could regulate lysosomal function by promoting Wnt/β-catenin signaling. In addition, in D-gal-induced aging and AD model mice, DBYW treatment activated Wnt/β-catenin signaling to restore lysosomal acidification, while spatial memory deficits in ARCD and AD models were improved, and pathology in mouse attenuation and APP/PS1 mouse brain tissue was inhibited.

CONCLUSION: DBYW shows a potential dual efficacy in improving cognitive decline in ARCD and AD models. It makes DBYW a promising disease-modifying intervention targeting the shared lysosomal pathophysiology of aging-associated neurodegeneration.},
}

@article {pmid41662521,
year = {2026},
author = {Boskovic, P and Shalita, R and Gao, W and Vernon, H and Deng, YL and Colonna, M and Majzner, RG and Amit, I and Kipnis, J},
title = {Engineering chimeric antigen receptor CD4 T cells for Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {7},
pages = {e2530977123},
doi = {10.1073/pnas.2530977123},
pmid = {41662521},
issn = {1091-6490},
support = {R01AG078667//HHS | NIH | National Institute on Aging (NIA)/ ; R61AG090394//HHS | NIH | National Institute on Aging (NIA)/ ; no number//Carol and Gene Ludwig Family Foundation/ ; no number//Cure Alzheimer's Fund (CAF)/ ; no number//Fred and Ginger Haberle Charitable Fund at East Texas Communities Foundation/ ; },
mesh = {*Alzheimer Disease/therapy/immunology/pathology ; *CD4-Positive T-Lymphocytes/immunology/metabolism/transplantation ; Animals ; *Receptors, Chimeric Antigen/genetics/immunology/metabolism ; Mice ; Humans ; Amyloid beta-Peptides/metabolism/immunology ; *Immunotherapy, Adoptive/methods ; Disease Models, Animal ; Brain/pathology/immunology/metabolism ; },
abstract = {Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8[+] cells, CD4[+] T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging. Here, we sought to exploit the beneficial properties of CD4[+] T cells while circumventing the need for TCR and peptide-MHC antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4[+] T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4[+] T cells into the brain parenchyma and leptomeninges. In summary, we established the feasibility of amyloid plaque-specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4[+] CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the CNS, paving the way for future development of cellular immunotherapies for neurodegenerative disease.},
}

*Alzheimer Disease/therapy/immunology/pathology
*CD4-Positive T-Lymphocytes/immunology/metabolism/transplantation
Animals
*Receptors, Chimeric Antigen/genetics/immunology/metabolism
Mice
Humans
Amyloid beta-Peptides/metabolism/immunology
*Immunotherapy, Adoptive/methods
Disease Models, Animal
Brain/pathology/immunology/metabolism

@article {pmid41661364,
year = {2026},
author = {Li, L and Kong, J and Fan, R and Yuan, Y and Zhu, L},
title = {Correction: Role of tRNA-Derived Fragments and Their Modifications in the Pathogenesis and Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {429},
doi = {10.1007/s12035-026-05713-2},
pmid = {41661364},
issn = {1559-1182},
}

@article {pmid41660277,
year = {2026},
author = {Fang, Y and Han, Z and Yang, S and Chen, J and Li, R and Zhang, Z and Song, J and Wang, D and Ban, Y},
title = {Ferroptosis and Alzheimer's disease: unraveling the molecular mechanisms and therapeutic opportunities.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1758041},
pmid = {41660277},
issn = {2296-634X},
abstract = {Ferroptosis is a novel form of regulated cell death. Compared with other types of cell death, it shows great differences in structure and biochemistry. This type of cell death is receiving increasing attention. For example, studies have found that it plays a key role in the development of neurodegenerative diseases underlying brain atrophy, such as Alzheimer's disease (AD). AD is a chronic and worsening neurodegenerative disease. It poses a serious threat to the health and quality of life of the elderly. The pathology of AD is mainly the presence of extracellular beta-amyloid (Aβ) plaques and intracellular tau-based nerve fiber entanglement (NFTs). Although there are a large number of studies and interventions for AD, so far, no clinical drugs have been found that can stop the pathological progression of AD or cure it. Currently, treatment strategies for this disease only focus on alleviating clinical symptoms and do not achieve slowing disease progression or curing it. Ferroptosis is gradually considered to play a key role in the occurrence and development of AD. Research based on the AD model confirms that neuronal ferroptosis can be inhibited through pharmacology to reverse cognitive disorders. In this review, we first describe the key molecular mechanisms of ferroptosis, and then discuss how these mechanisms operate and develop in AD. Then, we give a detailed introduction to the latest treatments for AD, including iron chelators, antioxidants, and specific ferroptosis inhibitors. What is noteworthy is that this article emphasizes the analysis of the mechanisms of iron metabolism disorders, as well as the introduction of new drugs for the prevention, rather than the alleviation of AD.},
}

@article {pmid41659595,
year = {2026},
author = {Chaggar, P and Vogel, JW and Thompson, TB and Aldea, R and Strandberg, O and Stomrud, E and Palqmvist, S and Ossenkoppele, R and Jbabdi, S and Magon, S and Klein, G and , and Mattson-Carlgren, N and Hansson, O and Goriely, A},
title = {Dynamical A β -Tau-Neurodegeneration Model Predicts Alzheimer's Disease Mechanisms and Biomarker Progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.27.701320},
pmid = {41659595},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease is characterised by the pathological interaction of two proteins, amyloid-beta (Aβ) and tau, which collectively drive neurodegeneration and cognitive decline. The progression of Aβ, tau, and neurodegeneration biomarkers is captured by the ATN framework, which is a powerful tool for disease classification. However, since the ATN framework is mainly descriptive, it cannot quantify or predict relationships between biomarkers over time. We address this limitation by introducing a dynamical ATN (dATN) model that mechanistically simulates the spatiotemporal progression of Aβ, tau, and neurodegeneration. The dATN model integrates mechanisms of prion-like protein aggregation of Aβ and tau, network-based tau propagation, Aβ-driven catalysis of tau progression, and tau-driven neurodegeneration. We calibrated the model using multimodal longitudinal imaging data from both the ADNI and BioFINDER-2 cohorts and show that it accurately fits longitudinal regional Aβ, tau, and neurodegeneration data. Using the dATN model, we show that Aβ-induced effects predict Braak-like cortical tau progression, that the spatial colocalisation of Aβ and tau is a crucial biomarker of disease acceleration, and that tau-driven atrophy strongly correlates with observed neurodegeneration. Furthermore, by integrating the disease progression model with pharmacokinetic-pharmacodynamic simulations, we present a powerful tool that facilitates regional evaluation of therapeutic strategies targeting Aβ, identification of critical intervention windows, and prediction of heterogeneous treatment effects across brain regions. This framework unifies mechanistic understanding with clinical imaging biomarkers, offering a quantitative approach for forecasting disease progression, testing mechanistic hypotheses, and optimising personalised treatment strategies in AD.

ONE SENTENCE SUMMARY: Colocalisation of A β and tau predicts regional tau progression and optimal A β -targeted intervention windows, while tau predicts neurodegeneration.},
}

@article {pmid41657474,
year = {2026},
author = {Kim, GH and Pyun, JM and Kang, D and Kang, SH and Koh, SH and Kim, JS and Moon, SY and Moon, WJ and Park, YH and Shim, Y and Yang, DW and Youn, YC and Jung, YH and Cho, H and Choi, H and Lim, JS and Park, KH and Choi, SH},
title = {A Protocol of Korean JOint RegistrY for ALZheimer's Treatment and Diagnostics (JOY-ALZ).},
journal = {Dementia and neurocognitive disorders},
volume = {25},
number = {1},
pages = {25-41},
pmid = {41657474},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: To assess the long-term effectiveness, safety, and economic viability of recently approved Alzheimer's disease (AD) therapies, as well as to evaluate the real-world application of novel diagnostics among AD patients with diverse comorbidities, comprehensive real-world data (RWD) analysis is essential. The Korean JOint RegistrY for ALZheimer's Treatment and Diagnostics (JOY-ALZ) endeavors to create a registry of RWD derived from clinical practice on new diagnostic methods and therapeutic agents for AD introduced in Korea since 2021.

METHODS: Participants must fulfill all the following: 1) be at least 19 years old; 2) be actively receiving, scheduled to initiate, or undergoing evaluation for any AD disease-modifying treatment; 3) have completed amyloid positron emission tomography or cerebrospinal fluid AD immunoassay (a positive result is not essential for participation); 4) have a clinical classification of cognitively unimpaired, mild cognitive impairment, or probable AD dementia. Data generated during routine care is segmented into a minimum dataset, extended dataset, and research-only dataset requiring extra consent. Assessments encompass clinical, cognitive, functional, neurobehavioral, neuroimaging, and biomarker evaluations, in addition to systematic monitoring of new AD treatments and their safety. Data are collected and monitored at baseline, at semiannual intervals during the initial 2 years, and then annually up to 2034. To date, 46 medical centers will participate in JOY-ALZ.

CONCLUSIONS: JOY-ALZ is expected to promote understanding of the long-term clinical outcomes, safety, and cost-effectiveness of recently introduced diagnostics and treatments for AD, thereby supporting the progress of precision medicine in AD care and diagnosis.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06889818.},
}

@article {pmid41657418,
year = {2026},
author = {Geiger, PC and Pennington, JS and Kueck, PJ and John, CS and Mayfield, HD and Kemna, RE and Burns, J and Vidoni, E and Honea, R and Li, Y and Mahnken, J and Morris, JK},
title = {Heat therapy in individuals at risk for Alzheimer's disease-methods for a randomized controlled trial.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1736108},
pmid = {41657418},
issn = {1664-2295},
abstract = {UNLABELLED: Heat therapy (HT) has been shown to improve peripheral blood glucose regulation in some populations, yet its effects on brain glucose metabolism remain largely unexplored. The chronic benefits of HT may arise in part from upregulation of heat-shock proteins (HSPs). These proteins play a crucial role in the stress response and modulate diverse processes such as proteostasis and cell signaling pathways, including that of insulin signaling. Understanding the impact of HT on both peripheral and central glucose metabolism, including the effects of varying temperatures, is essential for elucidating potential mechanisms underlying its brain benefits. The Feasibility of Improving Glycemia to prevent Alzheimer's Disease (FIGHT-AD) study is a randomized controlled trial that aims to investigate changes in blood and brain glucose regulation following 10 weeks of HT. Specifically, we will examine the peripheral biomarker responses to warm and hot HT and assess how these responses relate to brain metabolic changes in both treatment groups. This trial will be the first to quantify the effect of HT on cerebral glucose metabolism in individuals at metabolic risk for Alzheimer's Disease (AD). The FIGHT-AD trial will provide critical data to inform the design of future clinical trials targeting metabolic and brain health through HT.

CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT06023407.},
}

@article {pmid41661788,
year = {2024},
author = {McCormick, L and Bodla, AP and Rubin, RT},
title = {Very early onset dementias: Importance of differentiating from schizophrenia spectrum disorders.},
journal = {PLOS mental health},
volume = {1},
number = {3},
pages = {e0000107},
doi = {10.1371/journal.pmen.0000107},
pmid = {41661788},
issn = {2837-8156},
abstract = {Very early onset dementias and other neurodegenerative diseases often present with prominent behavioral disturbances and can be initially misdiagnosed as schizophrenia spectrum disorders. Differentiating a primary psychiatric condition from a neurodegenerative cause is important, because there are considerable differences in prognosis, treatment, and the services required for effective management. To illustrate the implications of misdiagnosis, we provide case examples of very early onset dementias, most of which were initially diagnosed as schizophrenia or other psychotic disorder, owing to their unusually young age of onset and initial behavioral presentations. We suggest how a clinician can differentiate schizophrenia from rarer, early onset neurodegenerative causes of altered behavior and mentation, including behavioral variant frontotemporal dementia (bvFTD), Wilson's disease, adult metachromatic leukodystrophy (MLD), Creuzfeldt-Jakob disease (CJD), and very early-onset Alzheimer's disease. Schizophrenia with prominent obsessive-compulsive (OC) symptoms is briefly discussed, given that OC symptoms can be a major feature of dementias with prominent behavioral components.},
}

@article {pmid41656099,
year = {2026},
author = {Ma, YN and Huang, X and Xia, Y and Song, P and Hu, X},
title = {Protein persulfidation: The missing link in Alzheimer's disease defense mechanisms.},
journal = {Drug discoveries & therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.5582/ddt.2026.01004},
pmid = {41656099},
issn = {1881-784X},
abstract = {Despite decades of research dominated by the amyloid-beta hypothesis, clinical treatment of Alzheimer's disease (AD) has yet to achieve a decisive breakthrough. This editorial advances an alternative pathological paradigm: the collapse of endogenous hydrogen sulfide (H2S) signaling represents a central failure point in the brain's intrinsic defense mechanisms against AD. We dissect the molecular cascade triggered by cystathionine γ-lyase (CSE) deficiency, focusing on how reduced persulfidation of glycogen synthase kinase 3β (GSK3β) directly promotes Tau hyperphosphorylation and subsequent neuronal injury. A critical message of this commentary is the need to dispel the oversimplified notion that sulfide supplementation alone can confer neuroprotection. Because H2S works within a narrow therapeutic window and has complex hormetic effects, untargeted dietary or environmental exposure cannot match the spatiotemporal precision of endogenous signaling. Instead, it may increase the risk of toxicity. By integrating analyses of transsulfuration metabolism, mitochondrial function, and nutritional status, we propose a precision medicine framework centered on brain-targeted delivery technologies and metabolic correction strategies to selectively restore compromised H2S signaling networks. This conceptual shift marks a new direction in AD research, shifting the focus from clearing toxic protein aggregates to restoring endogenous neuronal resilience.},
}

@article {pmid41654970,
year = {2026},
author = {Lu, W and Kawatani, K and Ren, Y and Nambara, T and Jia, L and Jeevaratnam, S and Lee, E and Martinez, PR and Izhar, T and Wang, N and Raulin, AC and Wszolek, ZK and Bu, G and Kanekiyo, T and Li, Y},
title = {CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01982-0},
pmid = {41654970},
issn = {1758-9193},
support = {R21AG065653, R01AG078615, 24A07//NIH, Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program/ ; },
}

@article {pmid41654149,
year = {2026},
author = {Yuan, J and Zhang, S and Dong, X and Han, D},
title = {Agrin at the Crossroads of Aging: A Pleiotropic Regulator in Age-Related Diseases.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108131},
doi = {10.1016/j.phrs.2026.108131},
pmid = {41654149},
issn = {1096-1186},
abstract = {Aging is a significant risk factor for numerous age-related diseases, and elucidating its key molecular mechanisms is crucial for disease prevention and treatment. Agrin, initially identified for its role in neuromuscular junction development, is an extracellular matrix protein. Recent studies have revealed its broad functions in maintaining tissue homeostasis and facilitating cellular signal transduction. During aging, alterations in the expression and function of Agrin may participate in the regulation of tissue repair, inflammatory responses, and intercellular communication, thereby influencing the onset and progression of various age-related diseases. This review systematically examines the central role of Agrin in age-related diseases such as Alzheimer's disease, ischemic stroke, myocardial infarction, osteoarthritis, and type 2 diabetes. Accumulating evidence indicates that Agrin exhibits a distinct ''double-edged sword'' characteristic across different disease stages or tissue contexts-exerting protective effects in some scenarios while promoting pathological progression in others. We summarize current findings on the involvement of Agrin in disease mechanisms, including the regulation of amyloid deposition, blood-brain barrier integrity, synaptic function, inflammatory responses, and tissue repair. Furthermore, we discuss potential Agrin-targeted therapeutic strategies. We propose that Agrin represents a critical molecular node linking aging mechanisms with multiple age-related diseases. A deeper understanding of its context-dependent functional switching and the development of precise targeting approaches hold substantial promise for the prevention and treatment of age-related pathologies.},
}

@article {pmid41653883,
year = {2026},
author = {Vanderlip, CR and Gillen, DL and Grill, JD and Stark, CEL},
title = {Digital memory assessments and plasma pTau217 enable efficient preclinical Alzheimer's trials.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100503},
doi = {10.1016/j.tjpad.2026.100503},
pmid = {41653883},
issn = {2426-0266},
abstract = {BACKGROUND: Preclinical Alzheimer's disease (AD) trials enroll cognitively unimpaired, amyloid-positive older adults; however, most remain clinically stable over typical trial durations. Limited near-term decline reduces statistical power and drives large sample sizes and high costs. Scalable enrichment strategies capable of identifying individuals most likely to decline are critically needed.

OBJECTIVES: To determine whether a brief digital memory assessment (DMA) and plasma phosphorylated tau 217 (pTau217), individually or combined, identify preclinical AD participants at elevated risk for cognitive and biological progression, and whether such enrichment reduces clinical trial sample-size requirements.

DESIGN: Analysis of data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study, a multicenter randomized clinical trial with 240 weeks of follow-up.

SETTING: Secondary-prevention trial conducted across sites in the United States, Canada, Australia, and Japan.

PARTICIPANTS: A total of 1,169 cognitively unimpaired adults aged 65-85 years who were amyloid-positive and completed both a baseline DMA and plasma pTau217 measurement.

MEASUREMENTS: Primary outcome was change in the Preclinical Alzheimer Cognitive Composite (PACC) over 240 weeks. Secondary outcomes included Clinical Dementia Rating-Sum of Boxes, Mini-Mental State Examination, Cognitive Function Instrument, and annualized change in amyloid PET, plasma pTau217, and tau PET.

RESULTS: Participants with both elevated pTau217 and low DMA exhibited the greatest cognitive decline and reached the 240-week PACC decline of the overall cohort 83 weeks earlier. Participants with neither marker showed minimal decline. Dual enrichment reduced sample-size estimates for a clinical trial from 3,252 to 818 participants per arm (75 % reduction). These individuals also demonstrated faster increases in plasma pTau217 and neocortical tau PET.

CONCLUSIONS: A brief DMA combined with plasma pTau217 identifies a subset of cognitively unimpaired, amyloid-positive older adults at highest risk for cognitive and biomarker progression. This dual-marker enrichment strategy enables smaller, shorter, and more cost-efficient preclinical AD trials and supports more targeted evaluation of preventive therapies.},
}

@article {pmid41653511,
year = {2026},
author = {Nie, RZ and Luo, HM and Wang, H and Yang, YR and Wang, YZ and Zhang, SZ and Feng, K and Li, YL and Chen, FY and Duan, CX and Chen, JY and Ma, T and Li, PF},
title = {The inhibitory mechanisms of PGG, a natural polyphenol enriched with gallate moieties, against Aβ42 amyloid aggregation: A unified experimental and molecular dynamics simulation study.},
journal = {Bioorganic & medicinal chemistry},
volume = {136},
number = {},
pages = {118584},
doi = {10.1016/j.bmc.2026.118584},
pmid = {41653511},
issn = {1464-3391},
abstract = {Alzheimer's disease currently affects over 44 million individuals worldwide. Inhibiting Aβ aggregation and preventing the formation of toxic Aβ oligomers were regarded as promising therapeutic approaches. Experimental studies demonstrated that 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose (PGG), a natural polyphenol enriched with gallate moieties, significantly inhibited Aβ42 oligomerization and amyloid formation both in vitro and in vivo, underscoring its potential as a promising lead compound for AD therapy. Nevertheless, the detailed molecular mechanisms remained mostly unknown. Herein, we employed relevant biophysical methods to investigate the inhibitory effects of PGG and its analogs on Aβ42 amyloid aggregation, particularly on oligomer formation, providing direct evidence for the influence of gallate moiety number on its inhibitory activity against Aβ42 amyloid aggregation. Moreover, we further conducted 1500 ns all-atom MD simulations to explore how PGG inhibited Aβ amyloid aggregation. The simulations revealed that PGG promoted the adoption of a more loosely packed conformation of the Aβ42 dimer, and completely prevented the helix-to-β-sheet conformational change. Moreover, the binding of PGG molecules to the Aβ42 dimer resulted in the disruption of the inter-peptide interactions, and dramatically weakened the intra-peptide contacts. We observed that, apart from the usual hydrogen bonds and hydrophobic interactions, both π-π and cation-π interactions were also detected between specific residues of the Aβ42 dimer and the gallate moieties of PGG. We believed that these results might provide novel insights into the mechanisms underlying the inhibitory effects of PGG on Aβ42 amyloid aggregation and further support its potential for AD prevention and treatment.},
}

@article {pmid41652334,
year = {2026},
author = {Allison, GO and McCage, S and Brandt, S and Presciutti, M and Walker, K and Cornelius, T and Parker, RA and Dams-O'Connor, K and Dickerson, B and Ritchie, C and Vranceanu, AM and Bannon, SM},
title = {"We can do this. That I learned.": A nonrandomized open pilot of Resilient Together for Dementia, a post-diagnosis dyadic intervention.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07059-9},
pmid = {41652334},
issn = {1471-2318},
support = {R01NR019982-01/NR/NINR NIH HHS/United States ; 1K24AT011760-01/AT/NCCIH NIH HHS/United States ; 1K23AG075188-01A1/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease and related dementias (ADRDs) are prevalent conditions that are stressful and elevate emotional distress in couples after diagnosis. Without treatment, emotional distress may become chronic and negatively affect couples' quality of life. We report results from an NIH Stage 1A open pilot of Resilient Together for Dementia (RT-ADRD), a novel, dyadic, skills-based intervention aimed at preventing chronic emotional distress in couples early after diagnosis. We describe results from our mixed-methods single arm feasibility study, including preliminary feasibility and acceptability of the intervention, and qualitative feedback from exit interviews. We also present exploratory analyses for change in outcomes and mechanisms of action.

METHODS: Six couples (N = 12 individuals) were recruited within six months of ADRD diagnosis by their diagnosing providers. Participants completed baseline assessments, participated in weekly RT-ADRD sessions together, then completed post-intervention assessments and one 60-min exit interview together.

RESULTS: RT-ADRD exceeded all a-priori feasibility and acceptability benchmarks (> 70%). Feedback from exit interviews suggested that participants had favorable impressions of the program and found the skills useful and relevant. Participants also offered perspectives on barriers and facilitators of engagement and program enhancement. In exploratory analyses, persons living with dementia exhibited significant reductions in perceived stress at post-intervention (p < .05; Cohens d > 0.8). Both persons living with dementia and their care partners exhibited statistically significant improvements in positive dyadic interactions measured by the Dyadic Relationship Scale (ps < .05); Cohens ds > 0.8).

CONCLUSIONS: RT-ADRD shows promise as a feasible and acceptable dyadic intervention delivered early after diagnosis. Results support a future NIH Stage 1B trial of RT-ADRD to establish definitive feasibility markers of both intervention and control before formal efficacy testing.

TRIAL REGISTRATION: This open pilot was registered on ClinicalTrials.gov (NCT06421545) on 05/20/2024.},
}

@article {pmid41651379,
year = {2026},
author = {Huang, X and Sun, YY and Qin, YR and Chen, H and Pan, TT and Zhao, SS and Cai, Q and Zhang, XS and Nie, XD and Feng, L and Hu, H and Tang, Y and Zhang, PZ and Zhong, ZY and Li, J and Lu, L and Meng, FH and Ma, QH},
title = {ApoE-directed CpG nano-immunoadjuvant ameliorates Alzheimer's-like pathology in mice.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114687},
doi = {10.1016/j.jconrel.2026.114687},
pmid = {41651379},
issn = {1873-4995},
abstract = {Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD.},
}

@article {pmid41651301,
year = {2026},
author = {Zeying, W and Houyu, L and Zhongbin, Y and Yu, T and Qi, H and Kun, H and Qihang, H and Yingnan, Z and Zhi, L and Xiaojing, L and Xueming, Z and Qiang, M and Jingye, Z and Caixia, S and Liran, H and Jing, J and Yan, S},
title = {D-Ribose-Induced Cytotoxicity in K562 Cells: RBKS-Dependent Disruption of Copper Homeostasis and Mitochondrial Function.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.01.062},
pmid = {41651301},
issn = {1873-4596},
abstract = {BACKGROUND: D-ribose, a highly reducing pentose sugar, can be phosphorylated by ribokinase (RBKS) to form ribose-5-phosphate (R-5-P). Elevated urinary D-ribose levels have been reported in patients with type 2 diabetes mellitus (T2DM) and Alzheimer's disease, implicating its potential role in disease pathogenesis. Previous investigations into D-ribose cytotoxicity have primarily focused on its non-enzymatic glycation activity, while alternative mechanisms remain underexplored. Since hemoglobin is a major in vivo target of glycation, this study utilized K562 cells-which retain inducible hemoglobin expression-to examine additional cytotoxic mechanisms of D-ribose.

METHODS AND RESULTS: CCK-8 assays demonstrated that D-ribose inhibited K562 cell proliferation in a concentration- and time-dependent manner, and this inhibitory effect was significantly enhanced in hemin-induced differentiated K562 cells. Conversely, RBKS overexpression promoted proliferation and alleviated oxidative stress in K562 cells. Transcriptomic analysis revealed that differentially expressed genes in D-ribose-treated cells were enriched in mineral absorption and oxidative phosphorylation pathways (KEGG), as well as in biological processes related to copper ion homeostasis (GO). RT-qPCR confirmed that both D-ribose treatment and RBKS knockout downregulated key copper homeostasis genes (e.g., SLC31A1, MT1F, ATOX1) and mitochondrial respiratory chain genes (e.g., COX17, COX11, MTATP8, MTND6), and were accompanied by a significant reduction in intracellular free copper levels.

CONCLUSIONS: These findings reveal a novel cytotoxic mechanism mediated by the RBKS-copper-oxidative phosphorylation axis in D-ribose-treated K562 cells, providing key insights into the intracellular role of D-ribose.},
}

@article {pmid41650025,
year = {2026},
author = {Hou, XH and Zhang, W and Kang, K and Jin, Y and Ren, P and Wang, L and Li, Z and Li, Y and You, J and Zhang, B and Ma, Q and , and Xie, F and Yu, JT and Feng, JF and Cheng, W},
title = {Proteomics reveals three molecular subtypes of Alzheimer's disease with distinct progression patterns.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71106},
doi = {10.1002/alz.71106},
pmid = {41650025},
issn = {1552-5279},
support = {2023YFC3605400//National Key R&D Program of China/ ; 2018YFC1312904//National Key R&D Program of China/ ; 2019YFA0709502//National Key R&D Program of China/ ; 2025ZD0546300//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; 82472055//National Natural Science Foundation of China/ ; 62433008//National Natural Science Foundation of China/ ; 82071201//National Natural Science Foundation of China/ ; 81971032//National Natural Science Foundation of China/ ; 92249305//National Natural Science Foundation of China/ ; 25TQ010//Shanghai Pilot Program for Basic Research-Fudan University 21TQ1400100/ ; 23JS1410100//Shanghai Science and Technology Commission Program/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 2022QD002//Research Start-Up Fund of Huashan Hospital/ ; 3030277001//Excellence 2025 Talent Cultivation Program at Fudan University/ ; 2019074//Shanghai Talent Development Funding for the Project/ ; 2018SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; B18015//111 Project/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/classification/pathology ; Disease Progression ; *Proteomics ; Male ; Female ; Aged ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Cognitive Dysfunction/cerebrospinal fluid/pathology ; Longitudinal Studies ; Atrophy/pathology ; Machine Learning ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) shows marked molecular heterogeneity. Defining biological subtypes may refine diagnosis and treatment.

METHODS: We analyzed cerebrospinal fluid (CSF) proteomics and longitudinal data from 550 participants in the Alzheimer's Disease Neuroimaging Initiative with up to 16.5 years of follow-up. We profiled 6361 proteins, applied machine learning to identify biological subtypes, and validated them in three independent cohorts.

RESULTS: Three AD subtypes were identified. Subtype 1, enriched in RNA metabolism pathways, showed the mildest atrophy and slowest cognitive decline. Subtype 2, characterized by axonogenesis-related pathways, exhibited the greatest CSF tau elevations, moderate atrophy, and intermediate decline. Subtype 3, associated with catabolic processes, showed the most severe atrophy and fastest progression. These patterns were consistently replicated across validation cohorts.

DISCUSSION: These findings demonstrate robust, biologically distinct AD subtypes linked to divergent molecular pathways, clinical features, and progression rates. Such refined stratification supports precision diagnostics and targeted therapeutic strategies.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/classification/pathology
Disease Progression
*Proteomics
Male
Female
Aged
tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Cognitive Dysfunction/cerebrospinal fluid/pathology
Longitudinal Studies
Atrophy/pathology
Machine Learning
Aged, 80 and over

@article {pmid41648425,
year = {2026},
author = {Nada, H and Yuan, S and Gaamouch, FE and Cho, S and Gabr, MT},
title = {Small Molecule Agonists of TREM2 Reprogram Microglia and Protect Synapses in Human Alzheimer's Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.19.700278},
pmid = {41648425},
issn = {2692-8205},
abstract = {Triggering receptor expressed on myeloid cells-2 (TREM2) is a key immune receptor in the central nervous system that regulates microglial phagocytosis, survival, and neuroinflammatory responses. TRME2 variants have been established as genetic risk factors for Alzheimer's disease (AD). However, the therapeutic development of TREM2 modulators has been limited to antibody-based approaches that face limitations in blood-brain barrier penetration and manufacturing scalability. Furthermore, there are no FDA approved TREM2 therapeutics available to date marking an unmet therapeutic gap. Herein, we report the identification of the first TREM2 small molecule submicromolar binders as a result of optimizing compound 4a to yield S9 with TREM2 binding affinity of 0.95 µM. S9 demonstrated robust TREM2 agonism in cellular assays where it induced proximal Syk phosphorylation, activated downstream NFAT transcriptional signaling, enhanced APOE internalization and microglial phagocytic capacity. Pharmacokinetic profiling of the optimized hits revealed S9 to exhibit improved drug-likeness compared to 4a with 7-fold enhanced aqueous solubility, superior metabolic stability, reduced intrinsic clearance and a 9-fold improved hERG safety margin. Functional validation in human iPSC-derived microglia confirmed that S9 suppresses amyloid-beta (Aβ)-induced IL-1β secretion through a TREM2-dependent mechanism. In human neuron-microglia co-culture models exposed to amyloid stress, S9 treatment preserved synaptic integrity as measured by PSD95 expression that indicates promising neuroprotective activity. Together, these findings establish S9 as a first-TREM2 submicromolar small molecule TREM2 agonist which is orally bioavailable with favorable pharmacokinetic properties and promising therapeutic potential for the treatment of Alzheimer's disease.},
}

@article {pmid41648171,
year = {2026},
author = {Kumar, V and Sanchez Franco, VM and Ferry, FS and Xie, Y and Hutson, AN and Zhang, YJ and Daniels, SD and Nguyen, DL and Spera, LK and Snyder, EM and Knauss, A and Sudhakar, SL and Duan, GY and Paul, EM and Tabuchi, M},
title = {Neuronal microscale biophysical instability mediates macroscale network dynamics shaping pathological manifestations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.20.697254},
pmid = {41648171},
issn = {2692-8205},
abstract = {UNLABELLED: Microscale biophysical alterations in neuronal dynamics can have profound implications for macroscale pathological outcomes in the brain. Despite the critical need to link neuronal perturbations to large-scale disease manifestations, few studies successfully bridge these hierarchical scales. Here, we bridge microscale biophysical variability within neuronal dynamics to macroscale disease-related phenotypes. We find that Drosophila models expressing tauopathy- and epilepsy-associated molecular mutations exhibit increased dynamic instability in the timing of action potential initiation, and microscale biophysical changes are manifested at the level of the macroscale global brain state. We show that variability in voltage-gated sodium channel currents during non-stationary channel inactivation may act as a microscale biophysical contributor to the increased dynamic instability observed in action potential timing. We also find that treatment with antiepileptic drugs stabilizes neuronal dynamics by modulating this variability in voltage-gated sodium channel currents. Finally, we show that neurons derived from human induced pluripotent stem cells (iPSCs) from patients with Alzheimer's disease and epilepsy exhibit analogous dynamic instability, which is reversible by administration of antiepileptic medications. Our results highlight how subtle microscale neuronal instabilities propagate and are amplified to produce macroscopic pathological phenotypes, providing new biophysical insights into neurological disorders and potential strategies for therapeutic intervention.

SIGNIFICANCE STATEMENT: Linking microscale neuronal changes to macroscale disease phenotypes remains a key challenge in neuroscience biophysics. Here, we show that subtle biophysical instability, such as variability in action potential timing and increased noise in voltage-gated sodium channel activity, can destabilize neuronal network integrity and cause systemic pathology. Stabilizing neuronal dynamics with antiepileptic drugs reverses tau-induced instabilities in a Drosophila disease model. Similar neuronal instabilities occur in fly neurons expressing epilepsy-linked sodium channel mutations and in human iPSC-derived neurons from Alzheimer's and epilepsy patients, revealing a shared cellular mechanism. These findings highlight that targeting microscale instabilities may offer a unifying therapeutic approach for complex neurological disorders.},
}

@article {pmid41645816,
year = {2026},
author = {Liu, W and Rao, X and Sun, W and Chen, X and Yu, L and Zhang, J},
title = {Radiofrequency electromagnetic fields in Alzheimer's therapy: emerging evidence and future prospects.},
journal = {Electromagnetic biology and medicine},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/15368378.2026.2627962},
pmid = {41645816},
issn = {1536-8386},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in humans. The accumulation of abnormal protein aggregates, including extracellular amyloid plaques and intracellular neurofibrillary tangles, is considered a key pathological hallmark of AD. Currently, the primary approach for treating AD is pharmacological treatment, which is only symptomatic and unable to cure or reverse the progression of AD. Increasing evidence suggests that radiofrequency electromagnetic fields (RF-EMFs) may attenuate the progression of AD and improve memory function. This article reviews the studies related to the application of RF-EMFs in the field of AD, including investigations at the cellular and molecular levels, in animal models, and in clinical applications. The therapeutic potential of RF-EMFs as an intervention for AD is discussed in the present review, along with current challenges and future research directions.},
}

@article {pmid41645766,
year = {2026},
author = {Li, W and Guo, Y and Wang, X and Yang, C and Zhu, J and Cao, Z},
title = {Design, synthesis and biological evaluation of donepezil-safinamide hybrids as dual AChE and MAO-B inhibitor for Alzheimer's disease treatment.},
journal = {Journal of enzyme inhibition and medicinal chemistry},
volume = {41},
number = {1},
pages = {2622769},
doi = {10.1080/14756366.2026.2622769},
pmid = {41645766},
issn = {1475-6374},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Donepezil/pharmacology/chemistry/chemical synthesis ; *Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Drug Design ; *Acetylcholinesterase/metabolism ; Animals ; Structure-Activity Relationship ; Mice ; *Monoamine Oxidase/metabolism ; Molecular Structure ; Dose-Response Relationship, Drug ; *Alanine/analogs & derivatives/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; Humans ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Male ; Blood-Brain Barrier/metabolism ; Benzylamines ; },
abstract = {Alzheimer's disease (AD) still lacks therapies that definitively halt its progression. Dual AChE/MAO-B inhibitors offer a promising strategy to address both symptoms and pathology. Here, we designed and synthesised a series of donepezil-safinamide hybrids. The optimised compound 28c was identified as a potent inhibitor of AChE (IC50 = 1.70 μM) and MAO-B (IC50 = 0.18 μM). Mechanistic studies indicated that 28c acts as a reversible mixed-type inhibitor of AChE and a competitive reversible inhibitor of MAO-B. Molecular docking and molecular dynamic simulations revealed that 28c could strongly and stably bind to MAO-B and AChE mainly through van der Waals interactions. Moreover, compound 28c demonstrated effective blood-brain barrier penetration, exhibited suitable stability in mouse plasma and brain homogenate, and showed a favourable safety profile both in vitro and in vivo. Furthermore, 28c could attenuate AD-related symptoms and exert hippocampal neuroprotection effect in vivo, highlighting its promise as an anti-AD candidate.},
}

*Alzheimer Disease/drug therapy/metabolism
*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Donepezil/pharmacology/chemistry/chemical synthesis
*Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis
*Drug Design
*Acetylcholinesterase/metabolism
Animals
Structure-Activity Relationship
Mice
*Monoamine Oxidase/metabolism
Molecular Structure
Dose-Response Relationship, Drug
*Alanine/analogs & derivatives/chemistry/pharmacology/chemical synthesis
Molecular Docking Simulation
Humans
*Neuroprotective Agents/pharmacology/chemical synthesis/chemistry
Male
Blood-Brain Barrier/metabolism
Benzylamines

@article {pmid41645728,
year = {2026},
author = {Lodhi, MS and Maisam, M and Khan, MT and Bibi, A and Wei, D and Mou, K},
title = {Targeted Nanodelivery of WGX50 and Curcumin via Gold Nanoparticles for Alzheimer's Therapy.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {3},
pages = {e71045},
doi = {10.1111/jcmm.71045},
pmid = {41645728},
issn = {1582-4934},
mesh = {*Curcumin/chemistry/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Gold/chemistry ; Animals ; *Metal Nanoparticles/chemistry ; Rats ; Male ; Disease Models, Animal ; Drug Delivery Systems ; Humans ; Blood-Brain Barrier/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Rats, Sprague-Dawley ; Nanoconjugates/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, posing a global health challenge. It affects millions of people, causing cognitive decline and a heavy burden on healthcare systems. Neuroinflammation is a key pathological feature of AD, often associated with the dysregulation of microRNAs such as hsa-miR-146a-5p. WGX50 (N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-acrylamide), a small molecule derived from Zanthoxylum bungeanum Maxim, has antioxidant and anti-inflammatory activities. While WGX50 demonstrates potent inhibition of neuroinflammation, its poor blood-brain barrier permeability may be improved using targeted delivery strategies. The current study aimed to design a novel nanoconjugate of WGX50 and curcumin with gold nanoparticles (AuNPs) to observe its therapeutic effects in a rat model. All nanoconjugates were synthesised as targeted (Cys-capped AuNPs with WGX50-insulin and curcumin-insulin) and non-targeted (without insulin). Immunohistochemical analysis revealed that both non-targeted (WGX50-NT) and targeted (WGX50-T) therapies have a significant effect in the rat model, with WGX50-T showing a more pronounced effect. The histopathology results of WGX50 and WGX50-T showed an approximate 80%-90% reduction in Aβ plaque deposition. The treatment with both curcumins targeted (C-T) and non-targeted (C-NT) formulations led to a significant reduction in Aβ levels in AD rats. Fluorescence microscopy confirmed that targeted delivery was more effective, potentially leading to better therapeutic outcomes. The expression levels of hsa-miR-146a-5p showed differential expression levels with targeted treatments correlating with lower expression levels, suggesting a role in modulating neuroinflammation and immune responses. Overall, these findings highlight the potential of targeted drug delivery systems in enhancing the efficacy of AD treatments.},
}

*Curcumin/chemistry/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/pathology/metabolism
*Gold/chemistry
Animals
*Metal Nanoparticles/chemistry
Rats
Male
Disease Models, Animal
Drug Delivery Systems
Humans
Blood-Brain Barrier/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Rats, Sprague-Dawley
Nanoconjugates/chemistry

@article {pmid41645578,
year = {2026},
author = {İlhan, A and Güneş, F and Ertürk, A and Anıl, B and Gülçin, İ and Koca, M},
title = {Acetylcholinesterase and Carbonic Anhydrase Inhibition Profiles of New 5-HMF Chalcones and Their Ester Derivatives.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {2},
pages = {e70198},
doi = {10.1002/ardp.70198},
pmid = {41645578},
issn = {1521-4184},
support = {TBTK-0097-8209//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; },
mesh = {*Carbonic Anhydrase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Molecular Docking Simulation ; *Chalcones/pharmacology/chemistry/chemical synthesis ; *Acetylcholinesterase/metabolism ; Structure-Activity Relationship ; Esters/pharmacology/chemistry/chemical synthesis ; Molecular Structure ; Dose-Response Relationship, Drug ; Carbonic Anhydrase I/antagonists & inhibitors/metabolism ; Carbonic Anhydrase II/antagonists & inhibitors/metabolism ; Humans ; Animals ; },
abstract = {Acetylcholinesterase (AChE) is one of the most important therapeutic targets in the treatment of neurological disorders such as Alzheimer's disease. In recent years, studies on the use of carbonic anhydrase (CA) inhibitors in the treatment of Alzheimer's disease have attracted considerable attention. In this study, novel benzene/5-HMF-chalcone hybrids and their benzoate esters were synthesized. Furthermore, the AChE, carbonic anhydrases I and II (CA I and II) inhibition potentials of the compounds were evaluated through in vitro enzyme inhibition assays and molecular docking studies to identify new potential drug candidate molecules. According to the inhibition results, the Ki values of the synthesized compounds were found to be in the range of 1.51-2.91 nM against AChE, 26.15-68.66 nM against CA I, and 27.91-107.04 nM against CA II. Molecular docking studies revealed that the compounds bind to both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, with Glide scores ranging from -5.76 to -8.50 kcal/mol. In contrast, the molecules interacted with the active site of CA I/II by coordinating with the catalytic Zn[2+] ion. All compounds complied with Lipinski's Rule of Five, indicating favorable drug-like properties. These results suggest that 5-HMF-chalcone hybrids and their benzoate derivatives could serve as promising scaffolds for the development of new anti-Alzheimer's agents. These findings suggest that 5-HMF-chalcone hybrids and their benzoate derivatives may be useful in establishing the structural basis of new anti-Alzheimer's agents.},
}

*Carbonic Anhydrase Inhibitors/pharmacology/chemical synthesis/chemistry
*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry
Molecular Docking Simulation
*Chalcones/pharmacology/chemistry/chemical synthesis
*Acetylcholinesterase/metabolism
Structure-Activity Relationship
Esters/pharmacology/chemistry/chemical synthesis
Molecular Structure
Dose-Response Relationship, Drug
Carbonic Anhydrase I/antagonists & inhibitors/metabolism
Carbonic Anhydrase II/antagonists & inhibitors/metabolism
Humans
Animals

@article {pmid41645328,
year = {2026},
author = {Xiao, J and Liu, Y and Peng, M and Ma, J and Lei, S and Chen, Y and Liu, S and Zhao, X and Lu, D and Sun, Q},
title = {ISX9 activates the Wnt/β-catenin signaling pathway and exerts neuroprotective effects in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01961-5},
pmid = {41645328},
issn = {1758-9193},
support = {82470591//National Natural Science Foundation of China/ ; 82273485//National Natural Science Foundation of China/ ; JCYJ20240813142838050//Shenzhen Basic Research Program/ ; 2022A1515010598 and 2024A1515012466//Natural Science Foundation of Guangdong Province/ ; },
abstract = {BACKGROUND: Defective Wnt/β-catenin signaling is closely associated with the pathogenesis of Alzheimer's disease (AD), thus validating this pathway as a therapeutic target for AD. ISX9 is a potent agonist of the Wnt/β-catenin pathway. However, it remains unknown whether ISX9 exerts anti-AD effects by enhancing the Wnt/β-catenin signaling pathway. We therefore explored the neuroprotective potential of ISX9 using both hippocampal neuron-derived HT22 cells and 5×FAD transgenic mouse model of AD.

METHODS: In HT22 cells, we employed the SuperTOPFlash reporter gene, Co-IP and Western blot assays to investigate the mechanism by which ISX9 activates the Wnt signaling pathway. The effects of ISX9 on the biological behavior of HT22 cells were further evaluated through MTT, BrdU and IF staining. To study the therapeutic effect of ISX9 on AD, six-month-old 5×FAD transgenic mice were randomly divided into four groups: WT, WT/ISX9, AD and AD/ISX9. The mice were intraperitoneally injected with ISX9 or vehicle at an interval of one day for 2 months. Behavioral tests were conducted to evaluate the cognitive and learning abilities of mice, while the expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, blood-brain barrier (BBB)-related proteins and the components of Wnt/β-catenin signaling were investigated.

RESULTS: Our results demonstrated that ISX9 potently activated Wnt/β-catenin signaling by promoting the association of LRP6 with AXIN1, and increased the viability and proliferation of hippocampal cells. At the behavioral level, ISX9 improved learning and memory abilities in 5×FAD mice, and ameliorated hippocampal neuronal damage. Furthermore, ISX9 treatment effectively reduced the expression of Aβ peptides, total Tau, and phosphorylated Tau (S404) proteins in the AD mice. Mechanistically, ISX9 exhibited its neuroprotective effects, activating the Wnt/β-catenin signaling pathway via potentiating the interaction of LRP6 with AXIN1, upregulating the expression of BBB-related proteins and downregulating neuroinflammatory factors in AD mice.

CONCLUSION: Our findings indicate that ISX9 potently activates the Wnt/β-catenin signaling pathway and confers cognitive protection in hippocampal cells and AD mice. This compound may serve as a promising therapeutic agent for the treatment of AD.},
}

@article {pmid41643605,
year = {2026},
author = {Kim, WS and Choi, J and Kim, SS and Kim, JH and Han, YE and Kwak, MJ and Oh, SJ and Lee, B and Cho, IH and Choi, CW and Hong, GS and Kim, MS},
title = {Vitisin B, extracted from Vitis vinifera, enhances memory function and neuroprotective effects in scopolamine-induced memory-impaired mice.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {196},
number = {},
pages = {119019},
doi = {10.1016/j.biopha.2026.119019},
pmid = {41643605},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and memory dysfunction, with prominent roles in cholinergic deficits and synaptic plasticity impairments. Vitisin B, a resveratrol tetramer derived from Vitis vinifera, exhibits potent antioxidant and neuroprotective properties. However, its potential to influence cognitive function in AD models remains inadequately explored. In this study, we first tested vitisin B in an in vitro model using SH-SY5Y cells exposed to scopolamine-induced cytotoxicity, where vitisin B significantly enhanced cell viability and promoted cell survival. We evaluated its therapeutic potential in vivo using both systemic administration and direct delivery into the third ventricle of the brain in a scopolamine-induced AD mouse model. Across both administration routes, vitisin B exerted a broad pro-cognitive effect, restoring multiple domains of learning and memory disrupted by scopolamine. Vitisin B recovered spatial working memory in the Y-maze, normalized exploratory activity in the open field, improved recognition memory in the novel object recognition (NOR) test, and enhanced long-term memory retention in the passive avoidance assay. This treatment restored cognitive function, alleviated cholinergic deficits, increased hippocampal brain-derived neurotrophic factor (BDNF) levels, and enhanced synaptic plasticity. These results suggest that vitisin B exerts reliable cognitive and neuroprotective effects through both systemic and cerebral administration, highlighting its potential as a promising therapeutic compound for restoring cholinergic function and enhancing hippocampal synaptic plasticity in AD.},
}

@article {pmid41642798,
year = {2026},
author = {Justo-Henriques, SI and Silva, RCG and Carvalho, JO and Pérez-Sáez, E and de São João, RMV and Ribeiro, O},
title = {Differential response to cognitive stimulation in moderate versus moderately severe Alzheimer's disease.},
journal = {Canadian journal of experimental psychology = Revue canadienne de psychologie experimentale},
volume = {},
number = {},
pages = {},
doi = {10.1037/cep0000395},
pmid = {41642798},
issn = {1878-7290},
abstract = {Alzheimer's disease (AD) is characterized by impairments across several neurocognitive domains, particularly memory and executive function. The study explored the effectiveness of an individual cognitive stimulation (iCS) program on cognitive outcomes in older adults with moderate to moderately severe AD. A multicentre randomized controlled trial was conducted with 80 Portuguese older adults (Mage: 83.0 ± 7.1 years) with AD. Participants were randomly assigned to either iCS (n = 39; 49%) or treatment as usual (n = 41; 51%). Alzheimer's Disease Severity (ADS) categorized two groups based on Mini-Mental State Examination score: 10-14 in the ADS moderately severe group and 15-20 in the ADS moderate group. In participants with moderate AD, iCS led to significant improvements in memory-related outcomes (particularly Memory Assessment Test) and a trend toward improvement in global cognition. In contrast, no significant effects were observed in participants with moderately severe AD. Meta-analytic comparisons and meta-regression confirmed a significant difference in intervention effectiveness between severity levels. iCS was significantly more effective in individuals with moderate AD than in those with moderately severe AD. This difference in responsiveness between severity levels was statistically confirmed (Q = 11.29, p < .001). iCS was effective in enhancing memory in individuals with moderate AD, with additional indications of global cognitive benefit. However, no meaningful effects were observed in participants with moderately severe impairment, suggesting diminished responsiveness to iCS as disease severity increases. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid41642483,
year = {2026},
author = {Alhajeri, MM and Abukhaled, Y and Alkhanjari, RR and Bassiouni, W and Al-Ali, H and Baig, A and Sembaij, SH and Al Muhairi, FA and Dimassi, Z and Hamdan, H and Abd-Elrahman, KS},
title = {Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01674-1},
pmid = {41642483},
issn = {1573-6830},
abstract = {Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.},
}

@article {pmid41642425,
year = {2026},
author = {Li, Z and Wang, X and Li, M and Zhang, G and Zhang, Y and Wang, X and Zhang, C},
title = {Exploring the relationship between Alzheimer's disease and colorectal/breast cancers using SEER database, Mendelian randomization, and transcriptomic data.},
journal = {Discover oncology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s12672-025-04136-0},
pmid = {41642425},
issn = {2730-6011},
support = {2024JH2/102600293//Liaoning province livelihood science and technology joint plan/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) and cancer are among the most prevalent age-related diseases. Despite previous research into their potential relationship, the nature of their association remains poorly understood. This study aims to examine the clinical characteristics of AD and various cancers using data from the Surveillance, Epidemiology, and End Results (SEER) database, investigate the causal relationship between AD and cancers through Mendelian randomization (MR) analysis, and identify potential shared underlying mechanisms through transcriptomic profiling.

METHODS: Clinical data from AD patients were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database, and survival analysis was conducted using Kaplan-Meier curves. For the two-sample Mendelian randomization (MR) analysis, data were obtained from genome-wide association study (GWAS) databases. Multiple MR approaches, including inverse-variance weighted, MR-Egger, and weighted median methods, were applied, along with assessments of heterogeneity and sensitivity to ensure the robustness and reliability of the results. Transcriptomic data for AD, colorectal cancer (CRC), and breast cancer (BC) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified through differential expression analysis, followed by functional enrichment analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.

RESULTS: A total of 42,768 cancer patients who died from AD were included from the SEER database. Survival analysis revealed a more favorable prognosis (p < 0.01) in patients younger than 65 years. Asian or Pacific Islander patients exhibited better survival outcomes compared with White patients. Regarding tumor sites, patients with uterine corpus cancer had the best prognosis, while lung cancer patients had the poorest outcomes. Patients who received surgery, radiotherapy, or chemotherapy showed significantly improved survival compared to those who received no cancer treatment. Higher household income and being married were also associated with better prognosis, although no significant difference was observed by gender. MR analysis demonstrated a significant positive causal relationship between AD and CRC, and a weak inverse relationship between AD and BC, suggesting that increased genetic susceptibility to AD is associated with elevated CRC risk and reduced BC risk. Intersection analysis of DEGs revealed that shared DEGs between AD and BC were enriched in GO terms related to amino acid transport regulation, organic acid transport regulation, positive regulation of vesicle docking, and myo-inositol transmembrane import. Shared DEGs between AD and CRC were enriched in presynaptic actin cytoskeleton organization, proteasome ubiquitin-independent protein catabolic process, negative regulation of cellular amide metabolic process, and adenylate cyclase binding. KEGG enrichment analysis indicated that AD and BC may share the synaptic vesicle cycle pathway.

CONCLUSION: Our study reveals significant subgroup heterogeneity among cancer patients who died from AD. MR analysis demonstrates that AD increases the risk of CRC while showing weak evidence for a decreased risk of BC. These associations may be mediated by mechanisms involving amino acid transport regulation, myo-inositol transmembrane import, and synaptic vesicle cycling. These findings offer new perspectives on the AD-cancer relationship and may guide future investigations into shared mechanisms.},
}

@article {pmid41641965,
year = {2026},
author = {Brenowitz, WD and Ehrlich, JR and Deal, JA and Yaffe, K},
title = {Introduction to Supplemental Issue: Sensory loss in Alzheimer's disease and related dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418685},
doi = {10.1177/13872877261418685},
pmid = {41641965},
issn = {1875-8908},
abstract = {Sensory impairments (e.g., decreased function in hearing, vision, olfaction, and other senses) may be risk factors for or early markers of Alzheimer's disease (AD) and related dementias (ADRD). Sensory impairments are common and have a large impact on wellbeing. Furthermore, they are clinically detectable and, often, treatable, and could be leveraged to identify and prevent AD/ADRD. This Supplemental Issue brings together original research articles, reviews, and thought papers regarding the links between sensory impairments and cognitive health. Together, this work highlights the significant opportunities to use sensory information and remediation for earlier diagnosis, treatment, and prevention of dementia.},
}

@article {pmid41641880,
year = {2026},
author = {Wieland, LS and Ludeman, E and Chi, Y and Feinberg, TM and Chen, IH and Chen, KH and Zhu, Y and Wolverson, E and Amri, H},
title = {Ginkgo biloba for cognitive impairment and dementia.},
journal = {The Cochrane database of systematic reviews},
volume = {2},
number = {},
pages = {CD013661},
pmid = {41641880},
issn = {1469-493X},
mesh = {Humans ; *Ginkgo biloba ; Randomized Controlled Trials as Topic ; *Cognitive Dysfunction/drug therapy ; *Dementia/drug therapy ; *Plant Extracts/therapeutic use/adverse effects ; *Phytotherapy/methods/adverse effects ; Bias ; Aged ; Cognition/drug effects ; Placebos/therapeutic use ; Activities of Daily Living ; Ginkgo Extract ; },
abstract = {BACKGROUND: Dementia is a neurocognitive disorder that interferes with cognition and independent functioning. Common dementia subtypes include Alzheimer's disease, vascular dementia, and mixed type. Mild cognitive impairment (MCI) is a risk factor for dementia, and subjective cognitive complaints may be the earliest manifestation. Although cholinesterase inhibitors may help reduce some cognitive and behavioral symptoms, there is no established treatment that cures or slows dementia progression. Ginkgo biloba (ginkgo) is a popular herbal preparation that is used to improve brain and circulatory health, and neuroprotective effects are biologically plausible.

OBJECTIVES: To assess the benefits and harms of Ginkgo biloba for the treatment of people with cognitive impairment or dementia.

SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE, Embase, four other databases, and two trials registries on 8 December 2022. The search was updated in MEDLINE, Embase, CENTRAL, and the trials registers on 18 November 2024.

SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ginkgo with placebo, usual treatment, or other treatments for cognitive problems in people with cognitive complaints or diagnoses of MCI or dementia.

DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, and assessed studies for risk of bias. Key outcomes were global clinical status, global cognitive function, activities of daily living (ADLs), adverse events (AEs), and serious adverse events (SAEs) at six months. When clinically appropriate, we pooled data using a random-effects model and expressed treatment effects as mean differences (MDs), standardized mean differences (SMDs), or risk ratios (RRs), each with its 95% confidence interval (CI). We used GRADE methods to assess the certainty of the evidence for each estimate.

MAIN RESULTS: We included 82 studies with 10,613 participants; 72 studies with 9783 participants provided extractable data. Four studies were at low risk of bias in all domains. Below we present data for the comparison of ginkgo versus placebo in people with different clinical conditions. Subjective cognitive impairment Three studies (597 participants) compared ginkgo with placebo for people with subjective cognitive complaints. Based on one study that lasted six months, it is uncertain whether ginkgo has any effect on global clinical status measured on a five-point Likert scale (MD 0.00, 95% CI -0.33 to 0.33; P = 1.00; 1 study, 197 participants; very low-certainty evidence). There were no data on cognition or ADLs. One study reported no difference in minor side effects between treatment groups and did not mention SAEs. A larger study lasting three months found that the risk of AEs may be higher with ginkgo versus placebo. It provided very uncertain evidence on the risk of SAEs. Multiple sclerosis and cognitive impairment Two studies (164 participants) tested ginkgo versus placebo over three months in people with multiple sclerosis and cognitive problems. Ginkgo probably has little or no effect on cognition measured on the Perceived Deficits Questionnaire (MD -0.09, 95% CI -0.41 to 0.22; P = 0.55, I² = 0%; 2 studies, 152 participants; moderate-certainty evidence). There were no data on global clinical status or ADLs. The studies suggested no important difference in numbers of AEs between groups, and there was no indication of SAEs due to ginkgo. Mild cognitive impairment Twelve studies (1913 participants) tested ginkgo against placebo in people with MCI. At six months, moderate-certainty evidence suggests that ginkgo probably has little to no effect on global clinical status measured on the Clinical Dementia Rating Scale (MD -0.03, 95% CI -0.06 to 0.01; 3 studies, 631 participants; I² = 0%), cognition measured on the Alzheimer's Disease Assessment Scale - cognition (MD -0.07, 95% CI -0.67 to 0.51; I² = 0%; 2 studies, 508 participants), and ADLs measured on the Instrumental ADL scale (MD -0.05, 95% CI -0.29 to 0.19; 1 study, 350 participants). There may be little or no difference between ginkgo and placebo at up to 12 months in the risk of AEs (RR 0.98, 95% CI 0.77 to 1.24; I² = 58%; 7 studies, 991 participants, 379 events; low-certainty evidence), and there is little or no difference in the risk of SAEs (RR 0.95, 95% CI 0.82 to 1.09; I² = 0%; 3 studies, 714 participants, 327 events; high-certainty evidence). Dementia Thirteen studies (3288 participants) compared ginkgo with placebo for dementia. At six months, low-certainty evidence suggests that people taking ginkgo may have better global clinical status on a six-point Likert scale (lower is better; MD -0.06, 95% CI -1.00 to -0.20; I² = 88%; 5 studies, 1359 participants), better cognition measured by decreases on a short cognitive performance test (Syndrom-Kurztest; MD -1.86, 95% CI -3.48 to -0.24; I² = 96%; 9 studies, 2801 participants), and slightly better ADLs measured on the ADL International Scale (MD -0.19, 95% CI -0.35 to -0.03; I² = 91%; 8 studies, 2571 participants). There is probably little or no difference between ginkgo and placebo in the risk of AEs at up to 12 months (RR 0.95, 95% CI 0.90 to 1.00; I² = 0%; 9 studies, 2746 participants, 1480 events; moderate-certainty evidence). There may be little or no difference in risk of SAEs at six months (RR 0.88, 95% CI 0.58 to 1.33; I² = 0%; 6 studies, 2463 participants, 89 events; low-certainty evidence).

AUTHORS' CONCLUSIONS: In people with cognitive complaints, we are unsure whether ginkgo improves global clinical status at six months, and it may be associated with an increased risk of AEs at three months. Ginkgo probably has no benefit at three months for cognition in multiple sclerosis; numeric data on AEs were unavailable, but studies did not suggest concerns. In people with MCI, ginkgo probably has little or no effect at six months on global status, cognition, or ADLS. There may be little or no difference in AEs, and there is little or no difference in SAEs, at up to 12 months. In people with dementia, there may be small to moderate benefits at six months for global status, cognition, and ADLs. There is probably little or no difference in AEs at up to 12 months, and there may be no difference in SAEs.},
}

Humans
*Ginkgo biloba
Randomized Controlled Trials as Topic
*Cognitive Dysfunction/drug therapy
*Dementia/drug therapy
*Plant Extracts/therapeutic use/adverse effects
*Phytotherapy/methods/adverse effects
Bias
Aged
Cognition/drug effects
Placebos/therapeutic use
Activities of Daily Living
Ginkgo Extract

@article {pmid41641771,
year = {2026},
author = {Ruan, Q and Zhang, C and Wu, P and Huang, K and Xiong, X and Qiu, Z and Song, X and Wu, H and Guo, J},
title = {Restoration of intracellular osmotic pressure balance induced by protein nanoparticles: A potential target for developing Alzheimer's disease treatment strategies.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00763},
pmid = {41641771},
issn = {1673-5374},
abstract = {The progressive accumulation of amyloid-β and glutamate in synapses is a characteristic feature of early-stage Alzheimer's disease. This study investigated the influence of transmembrane osmotic pressure on Alzheimer's disease pathogenesis using a fluorescence resonance energy transfer-based optical probe for intermediate filament tension. Cotreatment with amyloid-β and glutamate at predicted cerebrospinal fluid levels induced Alzheimer's disease-like neuronal injury. Probe-transfected cells were used to monitor intermediate filament tension, whereas cytoplasmic osmolality was measured using a freezing point osmometer under individual and combined treatment with amyloid-β and glutamate. The results showed that the combined treatment of 50 nM amyloid-β and 0.3 mM glutamate significantly elevated intermediate filament tension and osmotic pressure. Cellular experiments indicated that this increase resulted from the formation of intracellular protein nanoparticles through nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome formation and cytoskeletal depolymerization. Oligomers of 50 nm amyloid-β induced an outward membrane current, whereas 0.3 mM glutamate increased both amyloid-β-induced current and calcium signals. The increase in protein nanoparticle levels and Ca2+ signals promoted voltage-dependent nonselective cation and anion influx, resulting in upregulated osmotic pressure, which was closely associated with the sensitization of ion channels elicited by calmodulin and protein kinase C activation. The attenuation of intracellular protein nanoparticles and desensitization of ion channels by drug combinations effectively alleviated transmembrane osmotic pressure and Alzheimer's disease-like neuronal injury. Behavioral assays performed using Caenorhabditis elegans Alzheimer's disease models further confirmed the efficacy of drug combinations. Therefore, protein nanoparticle-induced osmotic pressure plays a pivotal role in Alzheimer's disease pathogenesis, particularly in response to amyloid-β and glutamate cotreatment. Restoring intracellular osmotic pressure seems to be a potential target for developing new effective therapeutic strategies for Alzheimer's disease.},
}

@article {pmid41641469,
year = {2026},
author = {Ye, Q and Gao, W and Feng, J and Li, X and Li, J and Yang, F and Li, L and Zi, M and Wu, X and Gao, H and Li, H},
title = {Spatial heterogeneity in microglia-complement crosstalk: Implications for synaptic pruning in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71185},
pmid = {41641469},
issn = {1552-5279},
support = {82105035//National Natural Science Foundation of China/ ; LH2023H064//Nature Science Foundation of Heilongjiang Province/ ; 2024065//Research Project of the Health Commission of Jiangsu Province/ ; HABZ202325//Huai'an Basic Research Project/ ; HABL202222//Huai'an Science and Technology Bureau/ ; ZHY2024-304//Research Project of the Traditional Chinese Medicine Administration of Heilongjiang Province/ ; },
mesh = {*Alzheimer Disease/immunology/pathology/metabolism ; *Microglia/metabolism/immunology ; Humans ; *Complement System Proteins/metabolism/immunology ; *Brain/pathology/immunology ; *Neuronal Plasticity/physiology ; *Synapses ; Animals ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss, as a key pathological feature in its early stages. Recent studies have highlighted the central role of microglia-complement interactions in synaptic pruning. This interaction exhibits significant spatial heterogeneity in AD, with activation patterns and functional manifestations varying across different brain regions and stages of disease. Therefore, this article systematically reviews the synergistic mechanisms of microglia and the complement system in physiological synaptic pruning. Additionally, the dynamic evolution of the complement-immune network during disease progression is analyzed, and the amplifying effect of genetic factors on the spatial heterogeneity of synaptic pruning is explored. Furthermore, current treatment strategies from both Western medicine and traditional Chinese medicine are discussed, emphasizing the potential value of combining these approaches for intervening in synaptic loss in AD.},
}

*Alzheimer Disease/immunology/pathology/metabolism
*Microglia/metabolism/immunology
Humans
*Complement System Proteins/metabolism/immunology
*Brain/pathology/immunology
*Neuronal Plasticity/physiology
*Synapses
Animals

@article {pmid41641384,
year = {2026},
author = {Lai, X},
title = {Intrinsic mechanical vibrations as a missing dimension in amyloid-β clearance: a mechanochemical hypothesis for Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1749562},
pmid = {41641384},
issn = {1663-4365},
abstract = {Alzheimer's disease is widely viewed as a disorder of disturbed amyloid-β (Aβ) homeostasis, yet it remains unclear why Aβ shifts from routine turnover to progressive retention and plaque growth in mid-life. This article advances a mechanochemical hypothesis: that age-related reductions in low-intensity mechanical vibrations in the head and neck-arising from everyday self-vocalization (speech, singing, humming) and physiological, non-hypoxic upper-airway motion during stable sleep-contribute to a gradual narrowing of the Aβ clearance bottleneck. Gentle vibrations transmitted through bone and soft tissue could, in principle, enhance interstitial mixing, reduce local supersaturation and nucleation, increase encounter rates at blood-brain barrier and meningeal-lymphatic interfaces, and augment perivascular and glymphatic transport. A sustained decline in this "intrinsic mechanical vibration" (IMV) dose in mid-life might therefore favor Aβ retention without any change in production. We bring together indirect lines of evidence that are compatible with this view, including sleep and glymphatic studies, neuromodulatory stimulation paradigms, music and singing interventions, and hearing-loss epidemiology, and we discuss domains that at first appear inconsistent, such as voice-heavy occupations and obstructive sleep apnea. We then outline a testable cascade that links behavioral and sleep changes in mid-life to reduced mechanical drive and impaired clearance, and we propose concrete experiments spanning human laboratory studies, clinical trials, animal models, and prospective cohorts. Whether ultimately supported or refuted, this IMV-clearance framework highlights mechanical forces as a potentially modifiable dimension of Alzheimer's disease risk and treatment response, alongside sleep, vascular health, and cognitive engagement.},
}

@article {pmid41641155,
year = {2025},
author = {Sánchez-Juan, P and Baz, P and Arrieta, E and Novick, D and Díaz-Cerezo, S and Cotton, S and Walker, C and Trueba Saiz, Á and Núñez, M},
title = {The diagnostic pathway of Alzheimer's disease in real-world clinical practice in Spain: results from the Adelphi Dementia Disease Specific Programme™.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1702805},
pmid = {41641155},
issn = {1664-2295},
abstract = {INTRODUCTION: There are challenges associated with the timely diagnosis of people with mild cognitive impairment (MCI) and Alzheimer's disease (AD), especially with the future introduction of amyloid-targeting therapies. This study evaluates the current diagnostic journey for MCI and dementia due to AD in Spain.

METHODS: This study used data from the Adelphi Real World Dementia Disease Specific Programme (DSP[TM]), a cross-sectional survey with retrospective data collection. The survey involved primary care physicians (PCPs) and hospital specialists with experience in managing and treating AD, along with their consulting patients, between January and July 2023 in Spain. Analyses were descriptive.

RESULTS: Physicians (N = 94; 44.7% PCPs, 38.3% neurologists) reported data for 723 patients. Most patients (78.9%) first consulted a PCP. The median (inter-quartile range) time since symptom onset to first consultation was 21.6 (6.1-48.2) weeks and, in those patients who were not diagnosed immediately, the time from first consultation to diagnosis was 13.0 (6.0-21.9) weeks if diagnosed by a PCP, or 28.9 (17.1-52.1) weeks if diagnosed by a specialist. The diagnosing physician was a specialist or a PCP for 83.2% and 16.8% of patients, respectively. In addition, the most used advanced diagnostic techniques were computed tomography scans and magnetic resonance imaging (57.2% and 43.3% of patients, respectively). CSF determination of AD biomarkers was conducted in 12.4% of patients and AD-specific blood biomarkers in 2.9%. Treatment was mostly initiated by neurologists.

CONCLUSION: The diagnostic process for people with MCI and AD could be accelerated by increased awareness of the disease, shorter referral times, and better access to specialized diagnostic services. This study shows limited use of AD-specific biomarker testing in Spain.},
}

@article {pmid41641094,
year = {2026},
author = {Wang, J and Braunstein, JB and Wolz, R and Harper, L and Locascio, T and McPherson, HE and Mohs, R and Pontecorvo, MJ and Burnham, SC},
title = {Interchangeability of blood-based biomarkers and PET to identify Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70196},
pmid = {41641094},
issn = {2352-8729},
abstract = {INTRODUCTION: Establishing interchangeability between blood biomarkers and amyloid-positron emission tomography (PET) could help identify patients who would benefit from novel amyloid-targeting therapies for Alzheimer's disease.

METHODS: Adult participants from the Global Alzheimer's Platform Foundation's Bio-Hermes study with clinical diagnosis of mild cognitive impairment/mild dementia and available amyloid-PET evaluations and Aβ42/40-based PrecivityAD[®] (by C2N Diagnostics) and/or phosphorylated tau at threonine 217 (p-Tau217 (research use Meso Scale Discovery, Lilly) were included. Interchangeability between plasma-based tests (per pre-established thresholds) and amyloid-PET stratifications was evaluated.

RESULTS: PrecivityAD (N = 537) and p-Tau217 (N = 531) plasma-based tests had high agreement with florbetapir-PET (overall percent agreement: 80.7% and 90.1%, respectively) and accurately selected patients identified as florbetapir-PET-positive (positive predictive value: 86.0% and 88.0%, respectively). Further, they were non-inferior to quantitative florbetapir-PET (at 37 Centiloids) for identifying positive florbetapir-PET visual reads.

DISCUSSION: Results support the hypothesis that blood biomarkers may be interchangeable with amyloid-PET criteria for selecting patients who may benefit from treatment with novel amyloid-targeting therapies.

HIGHLIGHTS: Interchangeability of plasma-based tests and amyloid-PET stratifications was demonstrated.Non-inferiority of plasma-based biomarkers to amyloid-PET for identifying patients with AD pathology was observed.High agreement between plasma-based test stratification and florbetapir-PET expert visual read was observed.},
}

@article {pmid41641000,
year = {2025},
author = {Khan, SA and Raza, K and Tiwari, P and El-Tanani, M and Rabbani, SA and Parvez, S},
title = {Mechanisms to medicines: navigating drug repurposing strategies in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1676065},
pmid = {41641000},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) represents a continuously advancing neurodegenerative condition distinguished by the unremitting deterioration of cognitive abilities and memory impairment, which significantly hampers daily functioning of life. In the absence of disease modifying treatments, it continues to pose a significant global challenge. Though symptomatic treatment exists, the inherent complexity involved with AD pathogenesis related to Aβ plaques, neurofibrillary tangles, neuroinflammation, oxidative stress, etc. poses a tremendous challenge to developing drugs. With the incidence of AD increasing yearly globally, research into already existing pharmacological agents has the potential to uncover a brighter future for breakthroughs in treatment strategy. A primary strategy to accelerate the development of AD therapies is drug repurposing: determining a new use for an existing known medication. Following innovative approaches like high-throughput screening, AI-based techniques, a number of classes of drugs originally designed for other diseases are now being tested to modulate the complex pathology mechanisms in AD. This review focuses on the therapeutic promise of drug repurposing as adjunctive to the much-needed renaissance in AD therapies. The review continues to focus on some promising repurposed drug candidates, methodologies applied, and the evaluation of the present status of drugs in the clinic. Apart from the information regarding mechanisms involved in AD, this review also complements case studies, challenges, and limitations along with the various drug repurposing strategies for AD. By understanding and harnessing the potential of existing pharmacological agents, we can expand therapeutic options and improve patient outcomes.},
}

@article {pmid41640998,
year = {2025},
author = {Kawabata, S},
title = {Therapeutic and preventive strategies based on the maladaptive plasticity hypothesis for Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1726144},
pmid = {41640998},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), the most common form of dementia, is characterized by two hallmark pathologies, amyloid plaques (APs) and neurofibrillary tangles (NFTs). Amyloid-β and tau, key components of APs and NFTs, respectively, are widely considered primary drivers of neurodegeneration in AD. In contrast, an alternative view proposes that network failure, arising from amyloid-β precursor protein-driven excessive/aberrant and maladaptive synaptic plasticity, underlies AD pathophysiology. Synaptic plasticity is indispensable for cognitive functions such as learning and memory; however, when dysregulated, it may lead to cognitive decline and accelerate the trajectory toward AD. This paper, based on this hypothesis, examines strategies to mitigate maladaptive plasticity while preserving adaptive plasticity, and proposes the potential of novel approaches for the prevention and treatment of mild cognitive impairment and AD, encompassing both activity-based interventions and pharmacological treatments. This hypothesis-driven framework offers a coherent perspective linking molecular, circuit, and cognitive levels of dysfunction in AD, and may guide more integrative, multi-level approaches to future preventive and therapeutic strategies, a direction increasingly emphasized in current experimental and clinical AD research.},
}

@article {pmid41640856,
year = {2026},
author = {Badalova, A and Stott, J and Leff, AP},
title = {Proper name anomia in people with Alzheimer's disease: implications for diagnosis and treatment-a systematic review.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {11},
pmid = {41640856},
issn = {3005-1940},
abstract = {Proper name anomia (PNA) is a common experience that can become unpleasantly amplified in people with Alzheimer's disease (AD). In this systematic review, we discuss the key cognitive stages where naming can fail: facial recognition, person-specific semantics, and proper-name retrieval. We examine claims that PNA is an early indicator of AD and review studies that have attempted to treat PNA in individuals with AD. Twenty-two eligible studies were included. The main findings are that individuals with AD frequently experience difficulties in recalling proper names at any point in the disease process, with the distribution of functional breakdown between the three key cognitive stages involved in successful naming being: facial recognition (19%), person-specific semantics (30%), and proper-name retrieval (40%). PNA can be an early manifestation of AD. Effective behavioural treatments are available for those whose naming difficulties occur at the retrieval stage, including trial-by-trial practice using vanishing cues and spaced retrieval. We also provide clinical recommendations regarding the diagnosis and treatment of PNA.},
}

@article {pmid41640724,
year = {2026},
author = {Hayashi, M and Morimoto, Y and Mikuzuki, L},
title = {Comparison of electroencephalogram waveforms in older patients with/without dementia after administration of midazolam: a prospective, observational comparative study.},
journal = {Journal of dental anesthesia and pain medicine},
volume = {26},
number = {1},
pages = {41-51},
pmid = {41640724},
issn = {2383-9309},
abstract = {BACKGROUND: Sedation with midazolam in older patients with severe dementia can cause reactions that differ from those encountered in healthy individuals. We hypothesized that one reason for this is that electroencephalogram (EEG) responses to midazolam in patients with severe dementia may differ from those encountered in healthy individuals. In this study, we aimed to examine the effects of midazolam on EEG findings in older patients with severe dementia and compare them with those observed in older adults without dementia.

METHODS: We included 25 patients aged ≥ 60 years, and allocated them to either the dementia (13 patients) or non-dementia (12 patients) group. Participants with a Mini-Mental State Examination score of ≤ 23, Functional Assessment Staging of Alzheimer's disease stage 6 or 7, and/or Clinical Dementia Rating of being "severe" were considered to have severe dementia. EEG electrodes were attached to patients' frontal pole (Fp2). Midazolam was administered until a modified Observer's Assessment of Alertness/Sedation (OAA/S) score of 2 was attained. Chi-square test, Mann-Whitney U test, and Wilcoxon signed-rank test were performed to assess between-group differences. Differences were considered statistically significant at P < 0.05.

RESULTS: The power of the delta wave at baseline and immediately before treatment was higher in patients with dementia than that in the patients without dementia. Conversely, the power of the alpha wave was lower in the dementia group in the sedated state of the OAA/S 2. Regarding the changes within each group, the theta and beta waves in the dementia group decreased after midazolam administration.

CONCLUSION: Regarding EEG waveforms in the frontal pole, administration of midazolam significantly decreased the power of the fast wave (alpha wave) and increased the power of the slow wave (delta wave) in older patients with severe dementia compared with that in older patients without cognitive decline.},
}

@article {pmid41636955,
year = {2026},
author = {Hu, F and Tang, NLS and Wang, H and Zheng, H},
title = {Resolving Heterogeneity in the Diagnosis of Alzheimer's Disease and its Progression Using Multimodal Data.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {1},
pages = {24},
pmid = {41636955},
issn = {1559-1166},
support = {No.2018SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; },
abstract = {UNLABELLED: Alzheimer’s disease (AD) is a complex and diverse illness that makes early detection extremely difficult. Most existing research utilizes data to identify biomarkers and more homogeneous subgroups to improve the detection, prediction of progression, and prognosis of AD. However, AD still suffers from a lack of appropriate biomarkers for early symptom detection and blurred boundaries between different subgroups. Here, an unsupervised clustering method known as similarity network fusion (SNF) was employed to analyze multimodal data from 972 subjects, including 370 with cognitively normal (CN), 565 with mild cognitive impairment (MCI), and 37 patients with AD. First, we constructed a similarity network for subjects using cognitive scores, genetics, and magnetic resonance imaging (MRI) related data, respectively. Then the SNF fusion method was employed to integrate the data, and spectral clustering was used to find subgroups sharing similarities across modalities. Our results indicated that the approach accurately diagnosed both current and prospective AD (~ 90%). Notably, we successfully identified two MCI subtypes with biological and clinical significance, validated by longitudinal studies of cognitive, clinical, fluid biomarkers and MRI-related features, dementia diagnosis, and pseudo-trajectory analysis. We also observed many dysregulated processes and signaling pathways between MCI subtypes, such as the GnRH signaling pathway, VEGF signaling pathway, and insulin signaling pathway. Overall, our research offers a distinctive viewpoint on the diversity of AD, and the more specific subtypes of MCI help create customized treatment plans.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12031-026-02474-4.},
}

@article {pmid41572662,
year = {2026},
author = {Martino-Adami, PV and Jessen, F and Brosseron, F and Bewernick, B and Domschke, K and Luppa, M and Wagner, M and Peters, O and Frölich, L and Riedel-Heller, S and Schramm, E and Ramirez, A and Dafsari, FS},
title = {Exploring blood-based biomarkers in late-life depression: Correlates of psychotherapeutic treatment outcomes.},
journal = {European psychiatry : the journal of the Association of European Psychiatrists},
volume = {69},
number = {1},
pages = {e18},
doi = {10.1192/j.eurpsy.2026.10153},
pmid = {41572662},
issn = {1778-3585},
support = {01KG1716//Bundesministerium für Bildung und Forschung/ ; 01ED2007A//Bundesministerium für Bildung und Forschung/ ; 2030-390661388//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; Biomarkers/blood ; Aged ; Male ; Female ; *Major Depressive Disorder/therapy/blood ; Middle Aged ; *Cognitive Behavioral Therapy ; Aged, 80 and over ; },
abstract = {BACKGROUND: Major depressive disorder is a prevalent and debilitating mental health condition contributing to a growing global burden. Late-life depression (LLD), affecting individuals over 60 years of age, is further associated with elevated risks for cardiovascular diseases, cognitive decline, and dementia. Treatment responses vary widely, potentially due to underlying neurodegeneration and cellular senescence. We aimed to explore blood-based biomarkers related to Alzheimer's disease and senescence-associated secretory phenotype (SASP) proteins, seeking to identify biological underpinnings of LLD and their association with response to psychotherapy.

METHODS: We performed a secondary analysis of the Cognitive Behavioral Therapy for Late-Life Depression (CBTlate) trial in 228 participants aged 60 years and older with a diagnosis of LLD. Depression trajectories were compared using clustering. In participants with available plasma samples, biomarker data were generated post hoc. We assessed associations between biomarkers and depression trajectories, biomarker dynamics, and their ability to predict treatment response.

RESULTS: Two depression trajectories were identified: persistently high stable Geriatric Depression Scale (GDS) scores (hsGDS) and decreasing scores over time (dGDS). The hsGDS group had more severe baseline depression (p = 2.88 × 10[-6]), anxiety (p = 4.39 × 10[-4]), and sleep disorders (p = 1.09 × 10[-3]), and was more likely to have a history of major depression (p = 0.01) and mild cognitive impairment (p = 0.01). Biomarker analysis revealed elevated baseline plasma neurofilament light chain (NfL, p = 2.51 × 10[-2]) and reduced C-X-C Motif Chemokine Ligand 5 (CXCL5, p = 2.83 × 10[-2]) in the hsGDS group. Including CXCL5 in predictive models improved trajectory differentiation (p = 3.94 × 10[-3]).

CONCLUSIONS: Cellular aging biomarkers like CXCL5 may improve understanding of LLD and guide personalized therapeutic interventions.},
}

Humans
Biomarkers/blood
Aged
Male
Female
*Major Depressive Disorder/therapy/blood
Middle Aged
*Cognitive Behavioral Therapy
Aged, 80 and over

@article {pmid41639713,
year = {2026},
author = {You, C and Wu, S and Zhang, Y and Li, Q and Cui, Y and Wu, Y},
title = {Exploration of borneol essential oil function in the treatment of Alzheimer's disease based on network pharmacology and experimental validation.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-026-05280-y},
pmid = {41639713},
issn = {2662-7671},
}

@article {pmid41639575,
year = {2026},
author = {Zetterberg, H and Bendlin, BB},
title = {Biofluid biomarkers in Alzheimer's disease and other neurodegenerative dementias.},
journal = {Nature},
volume = {650},
number = {8100},
pages = {49-59},
pmid = {41639575},
issn = {1476-4687},
abstract = {Biofluid-based biomarkers have transformed neurodegenerative disease research and care, providing insights into the molecular underpinnings of Alzheimer's disease (AD) and other neurodegenerative dementias. This Review provides an update on recent developments in biofluid-based biomarkers for amyloid-β (Aβ) pathology, tau pathology, neurodegeneration, glial reactivity, α-synuclein pathology, TAR DNA-binding protein 43 (TDP-43) pathology, synaptic pathophysiology and cerebrovascular disease-pathologies and processes that are all relevant to neurodegenerative dementias. Complementing longstanding cerebrospinal assays, improved technologies now facilitate the detection of molecules linked to neurodegenerative brain changes at very low concentrations in the blood. This promises to complement the clinical evaluation of suspected neurodegenerative disease in healthcare with molecular phenotyping biomarkers that will help to link the clinical symptoms to ongoing pathophysiological processes in the brain and improve how patients are referred to specialty clinics for initiation and monitoring of molecularly targeted treatments. Clinically relevant breakthroughs such as the use of anti-Aβ monoclonal antibodies to address Aβ pathology in AD serve as important proof-of-concept examples of how the field is advancing toward molecularly informed prevention and treatment. This Review provides an overview of the most established biofluid-based biomarkers currently in use and offers practical guidance on their interpretation and implementation in clinical settings.},
}

@article {pmid41639293,
year = {2026},
author = {Amr, Y and Gad, W and Leiva, V and Martin-Barreiro, C and Abdelkader, T},
title = {Comparative analysis of supervised and ensemble models with unsupervised exploration for alzheimer's disease prediction.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-37122-9},
pmid = {41639293},
issn = {2045-2322},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, with no known cure. Early detection of dementia, a primary manifestation of Alzheimer's disease, is critical to enable timely intervention and treatment planning. This study introduces ensemble learning models for predicting Alzheimer's disease and presents a comparative analysis between traditional machine learning and advanced ensemble models. The evaluation is conducted using the "Open Access Series of Imaging Studies" 2 (OASIS-2) dataset. Traditional models, including logistic regression, decision tree, support vector machine, and random forest, are benchmarked against ensemble models such as adaptive boosting, extreme gradient boosting, and a hyperparameter-tuned majority voting ensemble models. Performance is assessed using accuracy, precision, and the area under the receiver operating characteristic curve. Results show that ensemble models, particularly the optimized majority voting classifier, consistently outperform traditional methods. To complement the supervised comparison, exploratory unsupervised methods were applied using multiple correspondence analysis and k-means clustering to uncover latent structures in the dataset. By categorizing all variables, these unsupervised methods highlight patterns of clinical and demographic similarity. Unlike prior studies that focus solely on predictive accuracy, this work integrates supervised classification, ensemble learning, and unsupervised exploratory analysis within a unified framework. This combined approach enables both robust performance comparison and deeper insights into latent data structures relevant to Alzheimer's disease. All computational experiments were conducted using the Python programming language.},
}

@article {pmid41639038,
year = {2026},
author = {Haskell, AK and Kulas, JA and Carter, WE and Javens-Wolfe, J and Hinkel, RD and Moussaif, M and Smiley, JS and Lazaro, O and Robertson, S and Palkowitz, AD and Lamb, BT and Richardson, TI and Dage, JL and Chu, S and Johnson, T and Stancato, LF and Syed, AQ},
title = {Generation and characterization of iPSC-derived microglia for in vitro modeling of stimuli-specific neuroimmune responses.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {2},
pages = {e71117},
doi = {10.1002/alz.71117},
pmid = {41639038},
issn = {1552-5279},
support = {//Center for Medical Genomics at Indiana University School of Medicine/ ; //Indiana University Grand Challenges Precision Health Initiative/ ; U01AG088021/AG/NIA NIH HHS/United States ; U54AG065181/AG/NIA NIH HHS/United States ; U54AG090792/AG/NIA NIH HHS/United States ; },
mesh = {*Microglia/immunology/metabolism ; *Induced Pluripotent Stem Cells/cytology ; Humans ; Cell Differentiation ; Receptors, Immunologic/immunology/metabolism ; Membrane Glycoproteins/immunology/metabolism ; Phagocytosis ; Cells, Cultured ; },
abstract = {INTRODUCTION: Microglia are macrophage-like brain resident immune cells known to express numerous Alzheimer's disease risk genes. Here we generated a human induced pluripotent stem cell (iPSC) derived microglia cell culture model for use in neuroimmune modeling and therapeutic testing.

METHODS: We generated iPSC lines using episomal reprogramming for subsequent stepwise differentiation of iPSC-derived microglia (iMG) without commercial kits. We characterized the responses of this model to immunogenic stimuli and recombinant TREM2 antibodies.

RESULTS: The iMG expressed several key microglia signature genes and are morphologically and transcriptionally dynamic. iMG rapidly phagocytosed myelin debris and strongly changed expression of lipid homeostasis genes. iMG expressed TREM2 and increased TREM2 levels in response to IL-4. Recombinant TREM2 antibody treatment impaired iMG myelin phagocytosis and upregulated chemokines.

DISCUSSION: We validated our iMG model system for the evaluation of biological responses of human microglia-like cells to stimuli and pharmacological agents for their transcriptional and functional impacts.},
}

*Microglia/immunology/metabolism
*Induced Pluripotent Stem Cells/cytology
Humans
Cell Differentiation
Receptors, Immunologic/immunology/metabolism
Membrane Glycoproteins/immunology/metabolism
Phagocytosis
Cells, Cultured

@article {pmid41635250,
year = {2026},
author = {Xu, Z and Xu, W and He, J and Qian, J and Wang, H and Li, C and Zhou, X},
title = {β-Asarone Attenuates Neuroinflammation of Alzheimer's Disease by Activating Autophagy and Suppressing NLRP3 Inflammasome Assembly.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {2},
pages = {e70771},
doi = {10.1002/cns.70771},
pmid = {41635250},
issn = {1755-5949},
support = {LJHSQY26H280002//Central Zhejiang Science and Technology Innovation CorridorJoint Fund of Zhejiang Provincial Natural Science Foundation of China/ ; 2025CC02//Inhua Traditional Chinese medicine science and technology project/ ; 2025ZL061//Zhejiang Province Traditional Chinese medicine science and technology project/ ; 2024-3-094//Jinhua major key science and technology plan project/ ; },
mesh = {Animals ; *Allylbenzene Derivatives/pharmacology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Autophagy/drug effects/physiology ; *Anisoles/pharmacology/therapeutic use ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; Mice ; *Inflammasomes/metabolism/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Mice, Transgenic ; Male ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; Microglia/drug effects ; },
abstract = {AIM: Alzheimer's Disease (AD) is a neurodegenerative condition with poorly understood mechanisms and few effective treatments. β-asarone has shown potential in AD management, though its molecular actions require further clarification. This study investigates the mechanisms through which β-asarone exerts its effects using both animal and cellular models.

METHODS: In vivo, the 3×Tg-AD mice were administered β-asarone for 8 weeks. Learning and memory abilities were assessed via the Morris water maze and step-down tests. Histomorphological examination, immunofluorescence, immunohistochemistry, ELISA, transmission electron microscopy, and Western blotting were employed to detect pathological changes, neuroinflammation, and protein expression of relevant signaling pathway molecules. In vitro, Aβ was used to culture BV-2 cells to mimic the brain microenvironment in Alzheimer's disease; changes in neuroinflammation, autophagy, and NLRP3 inflammasome-related proteins were observed after treatment with β-asarone.

RESULTS: The administration of β-asarone resulted in enhanced cognitive performance in 3×Tg-AD mice, alongside a reduction in microglial apoptosis induced by Aβ. Additionally, β-asarone diminished the accumulation of Aβ and phosphorylated Tau, ultimately supporting neuronal survival. In both the hippocampal tissue and BV-2 cell models, treatment with β-asarone led to a downregulation of neuroinflammatory markers and modulation of autophagy-related proteins (Beclin-1, P62, ATG5, LC3-II/I), while concurrently suppressing components of the NLRP3 inflammasome (NLRP3, ASC, Caspase-1, cleaved Caspase-1). Notably, the autophagy inhibitor 3-MA counteracted the inhibitory effects of β-asarone on NLRP3 activation.

CONCLUSION: β-Asarone attenuates AD-related neuroinflammation by activating autophagy to inhibit NLRP3 inflammasome assembly.},
}

Animals
*Allylbenzene Derivatives/pharmacology
*Alzheimer Disease/drug therapy/metabolism/pathology
*Autophagy/drug effects/physiology
*Anisoles/pharmacology/therapeutic use
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors
Mice
*Inflammasomes/metabolism/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
Mice, Transgenic
Male
Amyloid beta-Peptides/metabolism
Mice, Inbred C57BL
Microglia/drug effects

@article {pmid41635245,
year = {2026},
author = {Wiatrak, B and Szeląg, A},
title = {Alzheimer's disease: Time to reassess research and clinical priorities.},
journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University},
volume = {},
number = {},
pages = {},
doi = {10.17219/acem/217199},
pmid = {41635245},
issn = {1899-5276},
abstract = {Alzheimer's disease (AD) remains one of the most pressing challenges in contemporary neurology, with growing evidence highlighting the limitations of the amyloid hypothesis and monomodal therapies. This editorial advocates for a shift toward multidimensional research and therapeutic frameworks that integrate molecular, electrophysiological, neuroimaging, and behavioral data. Emphasis is placed on the potential of microRNA-based biomarkers, electroencephalography (EEG) analysis, and non-invasive methods to improve early diagnosis. Emerging multimodal treatment strategies - including immunotherapy, neurostimulation, and nutraceuticals - are discussed alongside ethical and regulatory challenges in implementing novel interventions. The authors propose an integrated, patient-centered model that combines precision medicine with preventive approaches rooted in lifestyle, digital biomarkers, and AI-powered personalization. A paradigm shift toward systemic, translational, and ethically grounded strategies is urgently needed to meet the growing burden of AD.},
}

@article {pmid41634843,
year = {2026},
author = {Bellelli, F and Delrieu, J and van Kan, GA and Peluso, A and Soriano, G and Vellas, B and Angioni, D and Sourdet, S},
title = {Are pre-frail and frail amyloid positive individuals eligible to Lecanemab? A cross-sectional analysis from the Cogfrail real-world cohort.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01966-0},
pmid = {41634843},
issn = {1758-9193},
abstract = {BACKGROUND: Following the positive outcomes of the Clarity-AD trial, Lecanemab received marketing authorization from the European Medicines Agency (EMA) and is expected to become available across Europe. However, the trial did not specifically evaluate frailty, making it difficult to estimate the potential effects of Lecanemab among frail individuals. This study aimed to apply Lecanemab eligibility criteria-based on both the Clarity-AD trial and the Appropriate Use Recommendations (AUR) from the United States and France-to a real-world population of pre-frail and frail older adults with confirmed positive amyloid status, and to evaluate differences in frailty status between eligible and non-eligible patients.

METHODS: Eligibility criteria from the Clarity-AD trial, the American and the French AUR, were applied to all participants with confirmed amyloid positivity (n = 120), assessed through amyloid-PET (visual reading) or cerebrospinal fluid (CSF) analysis (Aβ42 levels or Aβ42/Aβ40 ratio). Frailty was defined using the Fried phenotype.

RESULTS: The median age of the sample was 82.0 years (IQR: 79-85); 65% (n = 78) were women, and 36.7% (n = 44) were frail. Overall, 20.0% (n = 24) met the Clarity-AD eligibility criteria, while 50.8% (n = 61) and 47.5% (n = 57) were potentially eligible according to the American and French AURs, respectively. Only 9.1% (n = 4) of frail individuals met the Clarity-AD criteria, compared to 26.3% (n = 20) of pre-frail participants (p = 0.042). In contrast, 50.0% (n = 22) and 45.5% (n = 20) of frail individuals were potentially eligible according to the American and French AURs, respectively.

CONCLUSION: Although less than one in five participants would have been eligible for the Clarity-AD trial, approximately half the cohort would be potentially treatable with Lecanemab under real-world recommendations. While a considerable proportion of frail patients may have access to Lecanemab treatment in real-life, the low proportion of potentially eligible frail individuals for Clarity-AD in our cohort indirectly suggests that frailty may have been underrepresented in the trial, raising concerns about the generalizability of its findings to this population. Caution is warranted when targeting amyloid burden without previously addressing the underlying frailty.

TRIAL REGISTRATION: NCT03129269.},
}

@article {pmid41634017,
year = {2026},
author = {Li, Y and Wang, H and Zhang, D and Wang, S and Li, Z and Li, J and Tai, S and Tong, D and Wang, B and Lu, D and Yuan, S and Sun, W and Yang, B and Bai, C and Wang, Q and Ding, J and Wang, Z and Gao, Y and Yu, H and Cui, K and Liu, C and Mao, J and Yao, Y and Liu, F and Wan, Y and Yuan, J and Liu, X and Zheng, J},
title = {Gut microbiota-dependent 24-hydroxycholesterol metabolism contributes to capsaicin-induced amelioration of Alzheimer's disease-like pathology in mice.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-68937-9},
pmid = {41634017},
issn = {2041-1723},
support = {82160558//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Dietary capsaicin intake appears to affect the pathogenesis of Alzheimer's disease (AD), while the underlying mechanisms remain unclear. Here, we found in human cohorts that moderate-to-high level of dietary capsaicin intake was associated with improved cognitive performance. Similarly, long-term oral capsaicin administration in male 5×FAD mice ameliorated AD-like pathologies and reshaped gut microbial composition. Gut microbiota transfer from capsaicin-treated mice produced similar effects of capsaicin intake. Moreover, capsaicin elevated the level of host 24(S)-hydroxycholesterol (24-HC), relating to the increase of gut Oscillibacter genus abundance. The 24-HC elevation enhanced microglial phagocytic activity in the brain, and inhibited proinflammatory factors production via liver x receptor β (LXRβ)-mediated transcriptional regulation. Finally, we observed elevation of 24-HC in plasma in AD patients with higher level of dietary capsaicin intake, which correlated with cognitive scores and plasma Aβ and p-tau biomarkers. These findings suggest the potential of capsaicin or capsaicin-rich diets in the prevention or treatment of AD and related diseases.},
}

@article {pmid41633894,
year = {2026},
author = {Kim, DH and Jo, HY and Oh, YJ and Lim, JR and Chae, CW and Jung, YH and Han, HJ and Lee, HJ},
title = {Folate receptor 1 activation suppresses high glucose-induced amyloidogenesis in neurons via STAT3/Nrf2 pathway-dependent mitigation of mitochondrial oxidative stress.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {},
number = {},
pages = {119074},
doi = {10.1016/j.biopha.2026.119074},
pmid = {41633894},
issn = {1950-6007},
abstract = {Diabetes is a major risk factor for diabetic encephalopathy (DE), which is closely associated with sporadic Alzheimer's disease. Folic acid (FA) receptor signaling can suppress generation of neuropathogenic amyloid-beta (Aβ) induced by high extracellular glucose, suggesting that enhanced activation of this pathway could be a therapeutic strategy against DE-associated dementia, but the precise molecular signaling mechanisms are unclear. We report that high glucose levels increased the expression of amyloid precursor protein (APP) and β-secretase (BACE1) in cultured neurons and concomitantly induced amyloidogenesis, while FA treatment suppressed high glucose-stimulated expression of APP and BACE1, Aβ release, and accumulation of mitochondrial reactive oxygen species. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was minimal under high glucose conditions, but was significantly upregulated together with downstream antioxidant enzymes following FA co-treatment. High glucose stimulation also increased folate receptor 1 (FOLR1) mRNA expression, suggesting a compensatory protective response. While treatment with 5-methyltetrahydrofolate (5-MTHF), the activated form of folate, did not significantly alter high glucose-induced upregulation of APP and BACE1, knockdown of FOLR1 mRNA reduced high glucose-stimulated Nrf2 expression and further augmented APP and BACE1 expression under high glucose conditions. Treatment with the STAT3 inhibitor 5'15-DPP also abolished high glucose-stimulated Nrf2 expression and increased APP and BACE1 expression levels. These findings indicate that FA/FOLR1 activation suppresses high glucose-induced amyloidogenesis by mitigating mitochondrial oxidative stress via STAT3/Nrf2 pathway signaling. In conclusion, present study suggests that the FA/FOLR1/STAT3/Nrf2 pathway is an effective therapeutic target for DE.},
}

@article {pmid41631871,
year = {2026},
author = {Sun, M and Lin, J and Li, S},
title = {Extracellular tau oligomers exert neurocytotoxicity by triggering mitochondrial dysfunction.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251414979},
doi = {10.1177/13872877251414979},
pmid = {41631871},
issn = {1875-8908},
abstract = {BackgroundAbnormal tau aggregation is implicated in the development of neurodegenerative diseases such as Alzheimer's disease (AD). The presence of tau in the extracellular space and the spread of tau between nerve cells is associated with its toxicity. At present, researchers are trying to treat AD by limiting, blocking or removing extracellular tau.ObjectiveTo investigate the molecular mechanism underlying the cytotoxicity of extracellular tau oligomers.MethodsThe morphology of tau oligomers was observed by transmission electron microscopy. The neurocytotoxicity of tau oligomers was examined using CCK-8 assay. The localization of tau oligomers in cells was observed by laser confocal microscopy. The influence of tau oligomers on apoptosis was detected by Hoechst 33342/PI double-staining, Annexin V/PI double-staining and flow cytometry. JC-1 staining, DCFH-DA staining and Fluo-4 AM staining were used to evaluate the effect of tau oligomers on mitochondria. Western blot analysis was used to investigate the mechanism underlying the effects of tau oligomers on apoptosis and autophagy.ResultsAfter treatment with tau oligomers, the viability of SH-SY5Y cells decreased, and a typical apoptotic morphology was observed. Tau oligomers can enter cells, decrease the mitochondrial membrane potential, increase reactive oxygen species levels and drive calcium levels up to disrupt calcium homeostasis. The cytotoxicity of tau oligomers is closely related to the induction of mitochondrial apoptosis and blockade of mitophagy.ConclusionsThis study provides a molecular mechanism for understanding the cytotoxicity of extracellular tau oligomers and provides a therapeutic target for the development of effective treatment strategies for tau-related diseases.},
}

@article {pmid41630792,
year = {2026},
author = {Sato, K and Niimi, Y and Kurihara, M and Ihara, R and Iwata, A and Iwatsubo, T},
title = {Utility of APOE testing for reducing ARIA under probabilistic stopping rates to treat with anti-amyloid therapy for ε4-homozygote patients: A simulation study.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100059},
pmid = {41630792},
issn = {2534-773X},
abstract = {BACKGROUND: APOE ε4/ε4 genotype increases the risk of Amyloid-Related Imaging Abnormalities (ARIA) from anti-amyloid antibody treatment (AAT). While guidelines recommend testing, its practical utility depends on the resulting probability (p) that treatment is actually withheld for ε4-homozygotes, which varies significantly across clinical settings.

OBJECTIVES: To quantify the Number Needed to Test (NNT) to prevent one ARIA event as a function of p of withholding AAT in ε4/ε4 patients.

DESIGN: A Bayesian simulation study using a Beta-Binomial model to analyze genotype-stratified contingency tables.

SETTING: Data were derived from two published, phase 3 clinical trials: Clarity-AD (lecanemab) and TRAILBLAZER-ALZ 2 (donanemab).

PARTICIPANTS: Aggregate data from source trials.

INTERVENTION: Simulation of varying treatment discontinuation probability p from 0 (none) to 1 (universal for ε4-homozygotes).

MEASUREMENTS: NNT to prevent one ARIA event (any ARIA-E, any ARIA-H, and symptomatic ARIA-E) and the fractional reduction in total ARIA events as a function of p.

RESULTS: NNTs increased (worsened) significantly as p decreased. Under the most conservative policy (p = 1), the median NNT to prevent one any ARIA-E event was 20-30 (lecanemab) and 15-25 (donanemab), yet this only reduced total ARIA events by 10-30%. The NNT to prevent one symptomatic ARIA-E (lecanemab) was substantially higher, at 70-90 (at p = 1).

CONCLUSIONS: The direct safety impact of APOE testing for ARIA mitigation is limited, even under universal discontinuation policies. Its primary value lies in supporting shared decision-making and operational planning rather than as a standalone safety lever.},
}

@article {pmid41630733,
year = {2025},
author = {Aliffia, D and Wihadmadyatami, H and Raihan, MZZ and Kustiati, U and Sanjaya, WBT and Aviana, AP and Nugrahaningsih, DAA and Widayati, WT and Karnati, S and Kusindarta, DL},
title = {C3H mouse model of Alzheimer's disease: Blood markers, proteomic biomarkers, cognitive ability, and histopathology.},
journal = {Open veterinary journal},
volume = {15},
number = {11},
pages = {5718-5726},
pmid = {41630733},
issn = {2218-6050},
mesh = {Animals ; *Alzheimer Disease/pathology/chemically induced/blood ; *Disease Models, Animal ; Male ; Mice ; Biomarkers/blood ; Mice, Inbred C3H ; *Cognition ; Proteomics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition, and the number of cases of AD is projected to increase each year. Developing an AD animal model has a major impact on studying the pathology of the disease and on developing therapies and treatments.

AIM: This study aimed to create an AD animal model using C3H mice by administering trimethyltin (TMT) via intraperitoneal injection. Hematological analysis, pathology, protein biomarkers, and behavioral assessments supported the findings.

METHODS: In this experiment, two groups were included: a non-treated group (normal mouse) and a treatment group (AD animal model). Each group consisted of four male C3H mice aged 8 weeks. The treatment group was intraperitoneally injected with 2.5 mg/kg of body weight TMT. Hematological analyses were conducted to assess the blood routine, while pathological changes in brain structure, particularly in the hippocampus, were examined using hematoxylin and eosin staining as well as Nissl staining. Additionally, proteomic profiling was used to analyze protein biomarkers associated with AD via liquid chromatography-high-resolution mass spectrometry. Behavioral analysis was conducted using the radial arm maze.

RESULTS: Hematological analysis revealed an increase in hematocrit, mean corpuscular volume, leucocytes, and neutrophil levels, whereas other parameters remained within the normal range. Histopathological analysis revealed neuronal loss and structural alterations in the pyramidal cell layers of the CA1 and CA3, the presence of inflammation, and neurofibrillary tangles. Proteomic analysis identified several protein biomarkers related to AD in the AD animal model, including amyloid beta, tau protein, apolipoprotein E, and Triggering Receptor Expressed on Myeloid cells. Behavioral analysis demonstrated significant cognitive and memory declines in AD animal models compared with non-treated animals.

CONCLUSION: The intraperitoneal administration of TMT in C3H mice effectively induces pathological changes in the brain that are related to AD. The observed pathological and behavioral changes in this AD animal model resemble those found in human cases of the disease. This model can serve as a valuable platform for studying the etiology, pathogenesis, and pathophysiology of AD, as well as testing new therapies.},
}

Animals
*Alzheimer Disease/pathology/chemically induced/blood
*Disease Models, Animal
Male
Mice
Biomarkers/blood
Mice, Inbred C3H
*Cognition
Proteomics